Monoterpenes for treating respiratory tract diseases, in particular bronchopulmonary diseases

ABSTRACT

The invention relates to the combined use of at least one monoterpene which can be applied systemically, in particular perorally, and at least one respiratory tract therapeutic agent which can be applied topically, in particular through inhalation, for the prophylactic and/or therapeutic treatment, in particular combination therapy and/or co-medication, of respiratory tract diseases, in particular bronchopulmonary diseases. Through the combined use of the systemic monoterpene with the topical, in particular inhaled respiratory tract therapeutic agent, the effect or efficiency of the topical or inhaled respiratory disease therapeutic agent can be increased significantly, in particular in a synergistic manner, on the one hand, and the required dosage thereof can be reduced significantly on the other hand, combined with the resulting advantages (e.g., avoidance or reduction of side effects).

This application is a National Stade filing of International ApplicationPCT/EP 2009/005931 (WO 2010/025821), filed Aug. 14, 2009, entitled“MONOTERPENES FOR TREATING RESPIRATORY TRACT DISEASES, IN PARTICULARBRONCHOPULMONARY DISEASES” claiming priority to German Applications DE10 2008 045 702.7, filed Sep. 4, 2008, and DE 10 2008 047 221.2 filedSep. 12, 2008. The subject, application claims priority to PCT/EP2009/005931, and to German Applications DE 10 2008 045 702.7, and DE 102008 047 221.2, and incorporates all by reference herein, in theirentirety.

BACKGROUND OF THE INVENTION

The present invention relates to the medicinal field of respiratorydisorders, in particular bronchopulmonary disorders, and to theirtreatment.

The present invention relates in particular to the joint use of,firstly, systemically, in articular orally, administrable monoterpenestogether with, secondly, topically, in particular inhalatively,administrable respiratory therapeutics for the prophylactic and/ortherapeutic treatment, in particular combination therapy orcomedication, of respiratory disorders or bronchopulmonary disorders.

The present invention furthermore relates to a combination therapeutic,in particular in the form of a kit, or a combination therapy forprophylactic and/or therapeutic treatment of bronchopulmonary disordersor respiratory disorders using a comedication of, firstly, systemicallyadministrable, in particular oral, monoterpenes and, secondly, topicallyadministrable, in particular inhalative, respiratory therapeutics.

The term respiratory disorders is to be understood as meaning a generalterm which refers to all, in particular inflammatory, disorders of boththe upper and the lower respiratory tracts and which encompasses bothacute and chronic disease states. Examples of respiratory disorders ofthe upper respiratory tract are, for example, inflammations of theparanasal sinuses (e.g. rhinosinusitis), and examples of respiratorydisorders of the lower respiratory tract are, for example, bronchialasthma, bronchitis and COPD.

The term “bronchopulmonary disorders” is a generic term in particularfor all, inflammatory and non-inflammatory disorders of the lowerrespiratory tract (i.e. the bronchial and pulmonary respiratory tracts)including in particular bronchial asthma, bronchitis and also chronicobstructive pulmonary diseases (“COPD”), and, in the context of thepresent invention, is used synonymously with the term “respiratorydisorders of the lower respiratory tract”.

Bronchial asthma, often simply referred to as asthma, is a chronicinflammatory disorder of the respiratory tract with chronic bronchialhypersensitivity or hyper-reactivity, inflammation or the bronchi andalso lack of bronchial clearance, where, as a result of the bronchialobstruction, there may be episodes of respiratory distress, a generaldistinction being made between non-allergic (intrinsic) and allergic(extrinsic) asthma; in addition, mixed types of allergic andnon-allergic asthma and mixed types of asthma and COPD are also known.Depending on the severity and the accompanying disease symptoms, inaccordance with the Guidelines of the GINA 2006 (“Global Initiative forAsthma”), the different asthma disease stages are classified as GINA Ito IV, stage 1 being intermittent asthma, stage 2 being mild asthma,stage 3 being moderate asthma and finally stage 4 being severe asthma.In the new classification (GINA 2007), the priority is asthma control,and a distinction is thus made between controlled, partially controlledand uncontrolled asthma.

In contrast, bronchitis generally refers to an inflammation of thebronchi, in particular the bronchial mucosa, a distinction being madebetween acute bronchitis on the one hand and chronic bronchitis on theother. According to the World Health. Organization (WHO), chronicbronchitis is defined as cough and election on most days during at leastthree months in two successive years, and it is one of the most frequentchronic disorders world-wide (about 15 to 25%) with consequently greatrelevance from a health-economical perspective. In the case of chronicobstructive bronchitis, there is a persistent bronchial obstructionwhich in most cases develops from a chronic bronchitis.

The term chronic obstructive pulmonary disease or COPD is used as acollective term for chronic obstructive bronchitis and pulmonaryemphysema, the term “obstructive” being the typical feature ofpersistent bronchial constriction. Classification depends on theseverity and the accompanying disease symptoms and is in accordance withthe GOLD guidelines (GOLD=Global Initiative for Chronic Obstructive LungDisease) as the different COPD disease stages from GOLD I to IV.

In the treatment of bronchopulmonary disorders, in particular ofrespiratory disorders of the type mentioned above, in cases of mild tomoderate severity use is frequently made of topical or local, inparticular inhalative or inhalable, respiratory therapeutics. Theseinclude, for example, inhalative bronchodilators andbronchospasmolytics, such as inhalative beta-2-sympathomimetics,inhalative anticholinergics, inhalative corticosteroids or the like.Owing to their only topical or local action, the inhalative respiratorytherapeutics mentioned above are frequently not capable of deploying thedesired therapeutic action, so that in most cases relatively high doseshave to be administered to achieve the desired therapeutic results, orelse in more serious cases systemic therapeutics, in particular based oncorticosteroids, have to be coadministered when required or even on apermanent basis. As a consequence of the high doses used and required,in many cases unwanted side-effects are observed, too. Occasionally, aninsufficient sensitivity of the abovementioned inhalative respiratorytherapeutics with respect, to the respiratory disorders to be treated isobserved. Finally, a purely topical, in particular inhalative, therapyof the abovementioned respiratory disorders is associated in particularwith the disadvantage that the use of inhalative respiratorytherapeutics does not always result in sufficient deposition in theperipheral respiratory tract since she smallest branches of therespiratory tract, such as, for example, terminal and respiratorybronchioli, can, in general, not be reached by inhalative therapy, inparticular when pulmonary function is reduced, such as, for example, insevere COPD.

Thus, for example, both for bronchial asthma and for COPD—in addition toa basic therapy with bronchodilators—topical or local, in particularinhalative or inhalable, corticosteroids are used from a certain degreeof severity. In addition, for severe bronchial asthma according to GINAIV, systemic, in particular oral, corticosteroids are additionallyemployed.

Inhalable or inhalative corticosteroids, in particular inhalable orinhalative glucocorticoids, synonymously also referred to as “inhalativecorticosteroids” or simply by the acronym “ICS”, belong to the mostimportant therapeutics for the topical or local, in particularinhalative, treatment of inflammatory respiratory disorders, inparticular for bronchial asthma and COPD. The principle of action in thecase of regular inhalation consists in a primarily topical or localdeposition in the respiratory tract, combined with a simultaneouseffective anti-inflammatory action by relatively small amounts ofsteroids.

On a local or topical level, inhalable corticosteroids, in particularglucocorticoids, reduce respiratory inflammation by inhibition ofcytokines and arachidonic acid metabolites (AA metabolites) which arereleased from activated respiratory epithelial cells and distalmacrophages lining she respiratory tract, i.e. alveolar macrophages.Depending on the noxious substance inhaled and the genetic disposition,facilitated by the different chemotactically and vasodilatorily actingmediators mentioned above, various white blood cells enter therespiratory tract causing either eosinophile infiltration in the case ofbronchial asthma or primary granulocyte infiltration in the case ofCOPD. This cell infiltration is known to be an important determinant inthe development of respiratory inflammation in bronchial asthma andbronchitis.

However, according to current international and national therapyguidelines, ICS are not employed during early stages of respiratorydisorders, but in particular only for mild persistent asthma (GINA II)and for moderate to severe COPD (GOLD III and IV), where in most casescontinuous therapy is required [cf., for example: (1) Global Initiativefor Chronic Obstructive Lung Disease, GOLD 2004, National Institute ofHealth NIH and National Heart, Lung and Blood. Institute NHLBI,Bethesda, USA, www.goldcopd.com; (2) National institutes of Health(Ed.), Global Strategy for Asthma Management and Prevention, NHLBI/WHOWorkshop Report, Bethesda, USA, U.S. Department of Health and HumanServices, 2002, Global initiative for Asthma, GINA 2004, www.gina.com;(3) British Thoracic Society, The British Guidelines on AsthmaManagement. Asthma in Adults and Schoolchildren, Thorax 2003, 58: 1-94;(4) R. Buhl et al., Leitlinie zur Diagnostik und Therapie von Patientenmit Asthma [Guideline for the diagnosis and therapy of asthma patients],Deutsche Gesellschaft für Pneumologie und Beatmungsmedizin, Pneumologie2006, 60: 139-1831. This acknowledged therapeutic strategy takes intoaccount the increasingly known side-effects of ICS and also aninsufficient sensitivity of ICS in COPD. For this reason, therapy withICS is reserved for moderate and severe COPD, this treatment not beingable to influence the progression of CUPID, however, but rather onlybeing able to reduce exacerbations (cf., for example: B. R. Celli,Chronic Obstructive Pulmonary Disease: From Unjustified Nihilism toEvidence-Based Optimism, Proc. Am. Thoracic Soc. 2006, 3: 58-65).

Naturally, for the clinical success of a topical therapy with inhalativecorticosteroids, in particular glucocorticoids, the decree of depositionand in particular also the distribution of the steroids in theperipheral respiratory tract is of direct relevance. But even if variousrespiratory aids for metered aerosols and powder preparations are usedoptimally, the success of the therapy is limited not only by the abilityof the patient to inhale optimally, but rather primarily by theprinciple of inhalation as a consequence of the insufficient, treatmentof the peripheral respiratory tract. Significant causes of this are thusinsufficient steroid deposition in the smallest branches of therespiratory tract (<10⁻⁸ mol/l) and the associated higher deposition ofsteroids on the mucous membranes of the mouth and the trachea. As aresult thereof, following bioadsorption, relatively small amounts ofsteroids frequently involuntarily also end up in the blood streamcausing typical steroid side-effects such as, for example, inhibition ofcortisol production, development of osteoporosis, cataract formation,etc. These side-effects, which are becoming increasingly known, havetherefore until now limited the therapeutic use of ICS for milder formsof COPD, although according to the therapy guidelines ICS are, dependingon the severity of the respiratory disorder, recommended at even higherdosages and in combination with other therapeutics including oralglucocorticoids for a period of two to three weeks. The actual cause ofthis is the insufficient deposition of ICS in the peripheral respiratorytract and, at least in COPD, a non-steroidal anti-inflammatory therapywhich is additionally required. As yet, the smallest branches of therespiratory tract, such as terminal and respiratory bronchioli, haveonly been able to be reached by a systemic therapy.

In addition to the therapeutic approaches mentioned above, more or lesstraditionally, ethereal oils or oil mixtures are also used inhalativelyfor a relatively short period of time for the symptomatic treatment of,for example, bronchitic conditions, and to facilitate expectoration incases of hypersecretion, in particular for colds. However, this is atherapy which does not address the causes and which is used inparticular only for mild, especially acute, respiratory disorders andcan be used for chronic and in particular severe respiratory disordersonly in a supportive manner, if at all.

The publications DE 43 19 554 C2, DE 43 19 556 C2 and WO 94/28895 A2,which belong to the same patent family, describe a combination therapywith, firstly, orally administered terpene compounds, in particular1,8-cineol or menthol, and, secondly, likewise systemic, in particularorally administered corticosteroids for the anti-inflammatory treatmentof chronic bronchial asthma requiring systemic steroids (“GINA IV”),where she use of the orally administered terpene compounds in thecontext of a continuous therapy is meant to reduce she need for systemiccorticosteroids. However, the administration of systemic corticosteroidsis associated with serious side-effects. Owing to these seriousside-effects of systemic corticosteroids, the combination therapydescribed therein is limited to serious forms of bronchial asthma (“GINAIV”). These publications neither describe any inhalative treatmentconcepts, nor, because of the degree of severity of the disorderstreated therein, are they even taken into consideration.

As a consequence, the prior-art treatment methods of bronchopulmonarydisorders or respiratory disorders often do not give the desiredtherapeutic result, or only with unwanted side-effects. In particular,the topical or local, in particular inhalative or inhalable, respiratorytherapeutics used according to the prior art (such as, for example, ICS)do not always have the desired therapeutic effect.

BRIEF SUMMARY OF THE INVENTION

Accordingly, it is the object of the present invention to avoid at leastsome of the above-described disadvantages of the prior art, or at leastto reduce them.

In particular, in the context of the present invention, an improvedand/or more efficient therapy for the treatment of respiratorydisorders, in particular bronchopulmonary disorders, is to be provided.

Furthermore, in the context of the present invention, an improvedefficacy or a broader application spectrum is to be enabled or achievedlocally or topically, in particular inhalatively administrablerespiratory therapeutics of the type mentioned above (such as forexample, inhalative bronchodilators and/or bronchospasmolytics includingsympathomimetics, phosphodiesterase inhibitors, parasympatholyticsand/or vagolytics, anticholinergics, corticosteroids etc.).

Surprisingly, the applicant has now found that the object illustratedabove can be achieved by using, in the context of a comedication,firstly systemically, in particular orally, at least one monoterpene(=systemically administrable component) and, secondly, —together or incombination therewith—at least one topically administrable, inparticular inhalative, respiratory therapeutic (=topically administrablecomponent) for the prophylactic and/or therapeutic treatment ofrespiratory disorders, in particular bronchopulmonary disorders.

Entirely unexpected in this context is in particular the fact that, inthe context of the present invention, a systemic, in particular orallyadministered monoterpene is capable of any interaction with arespiratory therapeutic which, in distinction thereto, is administeredonly locally or topically, in particular inhalatively, and isadditionally then also capable of enhancing the activity of the latterin an unexpected manner, preferably in a synergistic manner. In thisway, it is possible to increase the efficacy of the topical, inparticular inhalative, respiratory therapeutic, and it is thereforepossible to significantly reduce the administered dose thereof, combinedwith the associated advantages (for example avoidance or reduction ofside-effects etc.).

Accordingly, the present invention provides—according to a first aspectof the present invention—the use of, firstly, at least one systemicallyadministrable, in particular oral, monoterpene and, secondly, at leastone topically administrable, in particular inhalative, respiratorytherapeutic for the prophylactic and/or therapeutic treatment, inparticular combination therapy and/or comedication, of respiratorydisorders, in particular bronchopulmonary disorders.

In other words, the present invention provides the use of, firstly, atleast one monoterpene and, secondly, at least one respiratorytherapeutic for the prophylactic and/or therapeutic treatment, inparticular combination therapy or comedication, of respiratorydisorders, in particular bronchopulmonary disorders, where themonoterpene is administered systemically, in particular orally, and therespiratory therapeutic is administered topically, in particularinhalatively.

As demonstrated, surprisingly, by studies of the applicant, by using asystemic, in particular oral, monoterpene in a combination therapy witha topical, in particular inhalative, respiratory therapeutic in thecontext of the prophylactic or therapeutic treatment of respiratorydisorders, in particular bronchopulmonary disorders, the efficiency oractivity of the topical or inhalative respiratory therapeutic can beenhanced significantly, in particular in a synergistic manner. It iscompletely surprising and was not to be expected that the systemically,in particular orally, administered monoterpene is capable of enhancingthe activity or efficiency of the topical or inhalative respiratorytherapeutic in the manner found, since two entirely different, separatetypes of administration—namely systemic on the one hand and locally ortopically on the other hand—are used for the two active compounds to becombined (i.e. monoterpene on the one hand and respiratory therapeuticon the other hand).

This effect, discovered completely unexpectedly by the applicant, canpossibly—without wishing to adhere to a certain theory—be attributed tothe fact that systemic or oral administration of the monoterpene resultsin a certain amount of the systemically or orally administeredmonoterpene, in particular owing to diffusion and/or exhalationprocesses, passing unchanged into the respiratory epithelium, inparticular into the alveolar and/or bronchial epithelium, where it is“exhaled.”, and it is as a consequence found in relatively largeconcentrations on and in the epithelial cells, where it then encountersthe topically or inhalatively administered respiratory therapeutic andcan act together with the latter, in particular in a synergistic manner.

As a result of the lipophilicity of the monoterpenes, what is alsoobserved is a long-term storage in the epithelial cells in question,such that a long-term and uniform supply of monoterpenes in theepithelial cells in question is ensured, so that a long-term interactionwith the inhalative respiratory therapeutic is ensured.

In the manner described above, it is possible to increase the activityor efficiency of topical or inhalative respiratory therapeuticssignificantly, in particular in a synergistic manner, and tosignificantly reduce the employed doses thereof, combined with theassociated advantages (for example avoidance or reduction ofside-effects etc.). At the same time, by the combined action of,firstly, monoterpene and, secondly, topical or inhalative respiratorytherapeutic, the sensitivity to the topical or inhalative respiratorytherapeutic can be enhanced significantly; as a consequence, it may bepossible to not only reduce the dose of the topical or inhalativerespiratory therapeutic, but under certain circumstances also to makethe topical or inhalative respiratory therapeutic in question availablein the first place for certain respiratory disorders or for certainstages of the respiratory disorders mentioned above, where hitherto ithas been impossible to use the topical or inhalative respiratorytherapeutics in question owing to the lack of sensitivity.

For its part, the activity enhancement of the topical or inhalativerespiratory therapeutic as such can probably—again without wishing toadhere to a certain theory—be attributed to the steroid-like activitypotential, surprisingly found by the applicant, of the systemicallyemployed monoterpenes, in particular with respect to the inhibition ofinflammation mediators which are formed by various infectious, allergicand/or inflammatory stimuli and—owing to mucus hypersecretion—effect anincrease or exacerbation of the respective respiratory inflammation. Asprecursors of phytosteroids, isolated monoterpenes (such as, forexample, 1,8-cineol, menthol etc.) thus have a steroid-like activitypotential; that is, they inhibit inflammation mediators. In contrast,complete ethereal mixed oils stimulate prostaglandin production and showa reduced inhibition of leukotriene and cytokine production compared tothe dominating monoterpene as main fraction of the mixed oils inquestion; this is because the mixed oils also comprise substances whichstimulate cell activity and mediator production and thus do not act inan anti-inflammatory manner but may cause incompatibility reactions, sothat, as a consequence, ethereal mixed oils and oil mixtures generallyincrease cell activity and induce mediator production and mucusformation. In contrast, however, isolated monoterpenes inhibit mucushypersecretion by inhibiting mediator production; this is to beconsidered not as a secretolytic, but rather an anti-inflammatory, inparticular mucolytic, effect in the respiratory tract. These effectsare—in contrast to inhalative respiratory therapeutics (for example ICS)on their own or as a monotherapeutic—achieved in the entire respiratorytract, in particular in the entire lung, i.e. including the peripheryand the alveoli, only when monoterpenes are used. This is becausemonoterpenes, following systemic administration, in particular in theform of enteric capsules which dissolve in the small intestine, aretaken up into the bloodstream and, in accordance with their physicalproperties, released in the alveoli and thus pass into the exhaled air.As a consequence, monoterpenes are capable of mediating ananti-inflammatory action even in the smallest peripheral branches of therespiratory tract—in contrast to inhalative respiratory therapeutics ontheir own.

Based on the findings described above, the applicant has, surprisingly,for the first time succeeded in providing an efficient combinationtherapy for the prophylactic and/or therapeutic treatment of respiratorydisorders, in particular bronchopulmonary disorders, which proposes orrealizes, in the context of a comedication, the joint use of, firstly,at least one monoterpene which is to be administered systemically, inparticular orally, and, secondly, —in combination therewith—at least onerespiratory therapeutic be administered topically, in particularinhalatively.

It is to be understood that, in the preceding description and in thedescription that follows of the present invention, embodiments made foronly one aspect of the invention do, of course, also apply to the otheraspects of the invention, without this requiring explicit mention.

It is furthermore understood that, below, all stated amounts, doses andranges are to be understood such that, if required, in particular forindividual cases or relating to certain applications, one may deviatetherefrom without leaving the scope of the present invention. This is atthe discretion of the person skilled in the art.

The person skilled in the art is aware that, in the context of thecombination therapy according to the invention or in the context of theuse according to the invention, firstly, the monoterpene to beadministered systemically, in particular orally, and, secondly, therespiratory therapeutic to be administered topically, in particularinhalatively, can be administered at the same time or else at differenttimes. Both with a view to the systemic component and with a view to thetopical component, in each case a single daily dose may be suitable, orelse it may be preferred to divide the respective total daily doses intotwo or more individual administrations over the course of the day; thedecision is at the discretion of the person skilled in the art.

With respect to the monoterpene employed, this may be selected inparticular from mono- and bicyclic monoterpenes, preferably from thegroup consisting of monocyclic monoterpene alcohols, preferably menthol(for example L-menthol), and bicyclic epoxy-monoterpenes, preferablylimonene oxides, preferably 1,8-cineol, and also mixtures thereof,particularly preferably from the group consisting of menthol and1,8-cineol. Very particular preference according so the invention isgiven to using the monoterpene 1,8-cineol.

It has been found to be particularly effective according to theinvention to use the monoterpene as an isolated or single activesubstance (i.e. not to use a mixture of different monoterpenes orethereal oils or oil mixtures), of course together with a suitablepharmaceutical carrier or excipient and optionally together with othercustomary pharmaceutical auxiliaries and/or additives. However,according to the invention, in principle it is not excluded to use twoor more monoterpenes together, in particular as a mixture, although thisis far less preferred according to the invention.

The terpenes are a highly heterogenous and very large group of chemicalcompounds which can be derived biosynthetically from isoprene orisopentenyl units, where the biosynthesis takes place via activatedforms of these molecules, namely dimethylallyl pyrophosphate (DMAPP) andisopentenyl pyrophosphate (IPP); the units consist of five carbon atoms(C₅ units). More than 8000 terpenes and more than 30 000 of the closelyrelated terpenoids are known. In the systematic classification ofOrganic Chemistry, the terpenes belong to the lipids (secondary naturalproducts). The common building block of all terpenes is isoprene. Theterpenes belong to the secondary plant products.

More than 900 monoterpenes are known. All are synthesized by monoterpenesynthases from geranyl pyrophosphate (2,6-dimethyloctane). In shecontext of the present invention, preference is given to using mono- andbicyclic monoterpenes. Most monocyclic monoterpenes which can be derivedfrom p-menthane have a cyclohexane skeleton, whereas the bicyclescarane, thujane, pinane, bornane and fenchane and, more generally, alsoisobornylane and isocamphane are the most important parent compounds ofthe bicyclic monoterpenes.

Menthol for its part—synonymously also referred to as2-isopropyl-5-methylcyclohexanol or else as5-methyl-2-(1-methylethyl)cyclohexan-1-ol—is a monocyclic monoterpenealcohol, whereas 1,8-cineol—synonymously also referred to as eucalyptol,limonene 1,8-oxide, 1,8-epoxy-p-menthane or else as1,3,3-trimethyl-2-oxabicyclo-[2.2.2]-octane—belongs to the bicyclicepoxy-monoterpenes, more accurately to the limonene oxides.

In the context of the present invention, the monoterpene is usuallyemployed in an oral administration form, preferably in the form ofcapsules. Particular preference according to the invention is given tothe administration of the monoterpene in the form of an oral entericpreparation, in particular capsule, which does, however, dissolve in thesmell intestine. Very particular preference is given to oral entericpreparations, in particular capsules, which dissolve in the smallintestine, and which contain a single monoterpene, preferably1,8-cineol. Such products are commercially available (for exampleSoledum® capsules sold by Cassella-med GmbH & Co. KG or Maria ClementineMartin Klosterfrau Vertriebsgeselischaft mbH, Cologne, Federal Republicof Germany).

In general, the monoterpene is employed in effective, in particularpharmaceutically effective, amounts. Here, the dose of monoterpene mayvary within wide ranges. Usually, the systemically, in particularorally, administered monoterpene is administered in daily doses of from100 to 2000 mg/die, in particular from 200 to 1200 mg/die, preferablyfrom 300 to 1000 mg/die. In other words, the monoterpene which is to beadministered systemically or orally is generally prepared foradministration in a daily dose of from 100 to 2000 mg/die, in particularfrom 200 to 1200 mg/die, preferably from 300 to 1000 mg/die. It is to beunder stood that, if required, the person skilled in the art may deviatefrom the amounts mentioned above for individual cases or relating tocertain applications without leaving the scope of the present invention.

According to an embodiment which is particularly preferred according tothe invention, the monoterpene to be administered systemically or orallyis 1,8-cineol in the form of enteric capsules which dissolve in thesmall intestine, preferably in daily doses in the range of from 100 to2000 mg/die, in particular from 200 to 1200 mg/die, particularlypreferably from 300 to 1000 mg/die.

The daily doses mentioned above can advantageously be divided into one,two, or more individual administrations.

As illustrated above, in combination with the monoterpene to beadministered systemically, in particular orally, a respiratorytherapeutic to be applied topically is administered as comedication.Like the monoterpene used in accordance with the invention, in thecontext of the combination therapy according to the invention therespiratory therapeutic to be administered topically is employed ineffective, in particular pharmaceutically effective, amounts, too, wherethe person skilled in the art selects the respective doses depending onthe respiratory disorder which is the subject of the therapy and itsseverity and depending on the topical respiratory therapeutic used.

In general, the respiratory therapeutic to be administered topically andwhich is used according to the invention is an inhalative or inhalablerespiratory therapeutic.

According to the invention, the term respiratory therapeutic to beadministered topically, in particular inhalatively, is to be understoodvery broadly and encompasses in particular all medicaments andmedicament combinations known to the person skilled in the art fortreating bronchopulmonary disorders or respiratory disorders and whichare suitable for topical, in particular inhalative, administration.

In a manner which is preferred according to the invention, therespiratory therapeutic to be administered topically, in particularinhalatively, is selected from bronchodilators and bronchospasmelytics.The term bronchodilators refers to substances which widen or dilatebronchi and bronchioli and, in this manner, reduce respiratoryresistance, whereas the term bronchospasmolytics refers to substanceswhich reduce the bronchial muscle tone and in some cases inhibit therelease of mediator substances from mast cells and increase mucociliaryclearance.

In a manner which is preferred in accordance with the invention, therespiratory therapeutic to be administered topically, in particularinhalatively, is selected from the group consisting of (i)corticosteroids, in particular glucocorticoids; (ii) sympathomimetics,in particular betasympathomimetics, preferably beta-2-sympathomimetics;(iii) phosphodiesterase inhibitors; (iv) parasympatholytics and/orvagolytics; (v) anticholinergics; and also mixtures and combinations ofthe compounds mentioned above.

In a manner which is very preferred according to the invention, thetopical, in particular inhalative, respiratory therapeutic is selectedfrom the group consisting of corticosteroids, in particularglucocorticoids, beta-2-sympathomimetics and anticholinergics and alsotheir mixtures and combinations.

It is to be understood that, in the context of the combination therapyor use according to the invention, combinations of at least two or moretopical, in particular inhalative, respiratory therapeutics of the typementioned above are also considered.

As described above, in accordance with one embodiment of the invention,the topically administrable, in particular inhalative, respiratorytherapeutic may be a topical or inhalative corticosteroid, in particularglucocorticoid. The topical or inhalative corticosteroid, in particularglucocorticoid, may in particular be a compound from the groupconsisting of beclometasone, mometasone, budesonide, flunisolide,fluticasone, triamcinolone and their physiologically acceptablederivatives, in particular salts and esters, and also mixtures andcombinations.

The corticosteroids are a group of about 50 steroid hormones formed inthe adrenal cortex and also chemically comparable synthetic compounds,all corticosteroids being formed from the starting material cholesteroland having progesterone (delta-pregn-4-ene-3,20-dione) as a commonskeleton. According to their biological action and the site at whichthey are formed, the corticosteroids can be divided into three groups,namely the mineralocorticoids, the glucocorticoids and the androgens.The glucocorticoids preferably used in accordance with the inventionthus belong to the corticosteroids.

The doses at which the topical or inhalative corticosteroids, inparticular glucocorticoids, are employed may vary within wide ranges.The topical or inhalative corticosteroid, in particular glucocorticoid,is usually administered in daily doses of from 50 to 1000 μg/die, inparticular from 75 to 800 μg/die, particularly preferably from 100 to600 μg/die, or is prepared in particular for administration in a dailydose of from 50 to 1000 μg/die, in particular from 75 to 800 μg/die,particularly preferably from 100 to 600 μg/die. It is to be understoodthat, if required, the person skilled in the art may deviate from thevalues mentioned above for individual cases or relating to certainapplications without leaving the scope of the present invention.

According to an alternative embodiment, the topical or inhalativerespiratory therapeutic may be a sympathomimetic, in particularbetasympathomimetic, preferably beta-2-sympathomimetic. According to theinvention, particular preference is given to the use of inhalativebeta-2-sympathomimetics.

The term sympathomimetics denotes substances which mimic the action ofthe sympathetic nervous system. Specifically, betasympathomimetics(synonymously also referred to as “betamimetics”) act mainly onbetareceptors. Very specifically, the beta-2-sympathomimetics, which arepreferred in accordance with the invention, relax smooth muscles(beta-2-receptors) and have brochospasmolytic action.

The inhalative beta-2-sympathomimetics which are preferably employed inaccordance with the invention may be either short-acting betamimetics(SABA=short-acting beta agonists) or long-acting betamimetics(LABA=long-acting beta agonists). Examples of short-acting betamimetics(SABA) are in particular albuterol, fenoterol, hexoprenal in,levalbuterol, metaproterenol, orciprenalin, pirbuterol, reproterol,salbutamol and/or terbutalin. Examples of long-acting betamimetics(LABA) are in particular salmeterol and/or formoterol.

According to an alternative embodiment, the topical or inhalativerespiratory therapeutic may be an anticholinergic. Anticholinergics aresubstances which suppress the action of acetylcholine and also havebronchospasmolycic activity. Topical or inhalative anticholinergicswhich are preferably employed in accordance with the invention areipratropium, tiotropium and/or their physiologically acceptablederivatives, preferably salts, particularly preferably ipratropiumbromide and/or tiotropium bromide.

It is understood by the person skilled in the art that, in the contextof the use or combination therapy according to the invention, thetopical or inhalative respiratory therapeutics mentioned above may alsobe combined with one another.

In the context of the use or combination therapy according to theinvention, it may furthermore be intended to administer additionally atleast one further systemic, in particular oral, active compound. Thisadditional systemic, in particular oral, active compound may be selectedin particular from the group consisting of systemic phosphodiesteraseinhibitors, in particular theophylline; systemic leukotriene receptorantagonists, in particular montelukast, zaforlukast and pranlukast;systemic corticosteroids; and also mixtures and combinations thereof.

In the context of the use according to the invention, it is possible totreat any bronchopulmonary disorders or respiratory disorders.

In particular, the bronchopulmonary disorder may be an inflammatory ornon-inflammatory, in particular inflammatory, disorder of the upper orlower respiratory tract.

Furthermore, the bronchopulmonary disorder may be an inflammatoryrespiratory disorder, in particular a respiratory disorder which isinfection-exacerbated and/or requires steroids for treatment.

For example, the bronchopulmonary disorder may be bronchial asthma orbronchitis.

Furthermore, the bronchopulmonary disorder may be chronic obstructivepulmonary disorder (COPD), in particular a chronic obstructivebronchitis or a pulmonary emphysema.

Furthermore, the bronchopulmonary disorder may be a tobaccosmoke-induced, in particular nicotine-induced, acute or chronicrespiratory inflammation.

In the context of the use or combination therapy according to theinvention, it is also possible to treat early forms of COPD, inparticular stage 0 or I according to GOLD, or else early forms ofbronchial asthma, in particular stage 0 or I according to GINA.

In the context of the use or combination therapy according to theinvention, it is in particular also possible to treat early forms ofCOPD, in particular stage 0 or I according to GOLD, or else early formsof bronchial asthma, in particular stage according to GINA, and in thismanner it is possible to achieve exacerbation prophylaxis before orafter exacerbation or prevention or slowing down of the progression ofthe disease before or after exacerbation.

The present invention furthermore relates to the use of at least onesystemically administrable, in particular oral, monoterpene, preferably1,8-cineol, in particular as described above, for the in particularsynergistic enhancement of the activity of at least one topicallyadministrable, in particular inhalative, respiratory therapeutic in theprophylactic and/or therapeutic treatment of respiratory disorders, inparticular bronchopulmonary disorders.

Furthermore, according to yet a further aspect of the present invention,the present invention relates to the use of at least one systemicallyadministrable, in particular oral, monoterpene, preferably 1,8-cineol,in particular as described above, for the in particular synergisticenhancement of the anti-inflammatory and/or antioxidative activity oftopical, in particular inhalative, corticosteroids, in particularglucocorticoids.

Likewise, according to yet a further aspect, the present inventionrelates to the use of at least one systemically administrable, inparticular oral, monoterpene, preferably 1,8-cineol, in particular asdescribed above, for reducing the dose of topically administrable, inparticular inhalative, respiratory therapeutics, preferably inhalativecorticosteroids, in the prophylactic and/or therapeutic treatment ofrespiratory disorders, in particular bronchopulmonary disorders.

Furthermore, according so another aspect of the present invention, thepresent invention relates to the use of at least one systemicallyadministrable, in particular oral, monoterpene, preferably 1,8-cineol,in particular as described above, for inducing and/or enhancing thesteroid-permissive effect of topically administrable, in particularinhalative, respiratory therapeutics, preferably inhalativecorticosteroids, in the prophylactic and/or therapeutic treatment ofrespiratory disorders, in particular bronchopulmonary disorders.

According to a further aspect, the present invention also relates to theuse of at least one systemically administrable, in particular oral,monoterpene, preferably 1,8-cineol, in particular as described above,for avoiding or reducing habituation to betasympathomimetics in theprophylactic and/or therapeutic treatment of respiratory disorders, inparticular bronchopulmonary disorders, in particular with continuoustherapy of all degrees of severity of COPD and bronchial asthma.

Moreover, according to a further aspect, the present invention relatesto the use of at least one systemically administrable, in particularoral, monoterpene, preferably 1,8-cineol, in particular as describedabove, in combination with at least one topically administrable, inparticular inhalative, respiratory therapeutic, in particular incombination with an inhalative corticosteroid, for reducing the need foror for replacing systemic corticosteroids or other antiinflammatoryand/or immunosuppressive systemic substances in the prophylactic and/ortherapeutic treatment of respiratory disorders, in particularbronchopulmonary disorders.

Furthermore, according to yet a further aspect of the present invention,the present invention relates to the use of at least one systemicallyadministrable, in particular oral, monoterpene, preferably 1,8-cineol,in particular as described above, in combination with at least onetopically administrable, in particular inhalative, respiratorytherapeutic, in particular in combination with an inhalativecorticosteroid and optionally further with an inhalativebeta-2-sympathomimetic, to optimize the basic therapy of bronchialasthma and COPD.

In the context of the uses according to the invention, it is alsopossible to treat systemic simultaneously affected organs in all severeforms of COPD.

The use according to the invention likewise serves to modulate andinhibit COPD-dependent and/or COPD-independent ageing processes, inparticular with the aim of reducing morbidity, increasing the quality oflife and/or life expectancy (“anti-ageing”).

Furthermore, in the context of the use according to the invention, themonoterpene, in particular 1,8-cineol, can be used as an inducer ofNO-production for the treatment of primary and secondarypulmonary-arterial hypertension (PAH) in COPD and bronchial asthma.

Furthermore, in the context of the use according to the invention, themonoterpene, in particular 1,8-cineol, can be used for improving tissueperfusion and/or microperfusion and also bronchodilation inNO-deficiency situations.

Likewise, in the context of the use according to the invention, themonoterpene, in particular 1,8-cineol, can be used for inducingNO-production in recurrent infections of the upper and lower respiratorytracts or in infection-independent exacerbations, in particular owing tocigarette smoking and/or the action of ozone, or for normalizing noxioussubstance-dependent or -independent NO-deficiency situations.

Likewise, in the context of the use according to the invention, themonoterpene, in particular 1,8-cineol, can be used as an antioxidantand/or NO-inducer in cigarette smoke-induced organ damage, in particularof the lung, the heart, the brain, the kidneys and the venous andarterial vascular system.

Likewise, in the context of the use according to the invention, themonoterpene, in particular 1,8-cineol, can be used for the combinedanti-inflammatory and/or antioxidative, therapy of the persistent and/orprogressive inflammation of the respiratory tract after cessation ofsmoking, if appropriate with comedication with other respiratorytherapeutics, in particular with the aim of delaying the development ofemphysemas, respiratory insufficiency and/or the development, ofperipheral airway obstructions.

Likewise, in the context of the use according to the invention, themonoterpene, in particular 1,8-cineol, can be used for modulating theentire multiorgan ageing process by virtue of anti-inflammatory and/orantioxidative effects in an early long-term therapy.

The present invention furthermore provides, according to vet a furtheraspect of the present invention, the use of at least one systemicallyadministrable, in particular oral, monoterpene and at least onetopically administrable, in particular inhalative, respiratorytherapeutic as combination therapeutic and/or for the purpose ofcomedication for the prophylactic and/or therapeutic treatment ofrespiratory disorders, in particular bronchopulmonary disorders.

The present invention yet further provides the use of at least onesystemically administrable, in particular oral, monoterpene and at leastone topically administrable, in particular inhalative, respiratorytherapeutic for preparing a combination therapeutic, in particular inthe form of a kit, for the prophylactic and/or therapeutic treatment ofrespiratory disorders, in particular bronchopulmonary disorders.

Likewise, the present invention also provides a combination therapeutic,in particular in the form of a kit, preferably for the prophylacticand/or therapeutic treatment of respiratory disorders, in particularbronchopulmonary disorders, where the combination therapeutic comprises,firstly, at least one systemically administrable, in particular oral,monoterpene and, secondly, at least one topically administrable, inparticular inhalative, respiratory therapeutic, in particular asspatially separate components (“kit-of-parts”).

The present invention furthermore also provides a method for treatingthe human or animal body, in particular a method for the prophylacticand/or therapeutic treatment of respiratory disorders, in particularbronchopulmonary disorders, where at least one monoterpene and at leastone respiratory therapeutic are each used in effective, in particularpharmaceutically effective, amounts, where the monoterpene isadministered systemically, in particular orally, and the respiratorytherapeutic is administered topically, in particular inhalatively.

The present invention yet further provides the use of at least onesystemically administrable or administered, in particular oral,monoterpene, preferably 1,8-cineol, for the prophylactic and/or curativetreatment of respiratory disorders, in particular bronchopulmonarydisorders, in smokers and/or former smokers (i.e. in active as well aspassive smokers) and for the preparation of a medicament for theprophylactic and/or curative treatment of respiratory disorders, inparticular bronchopulmonary disorders, in smokers or former smokers.Here, the monoterpene can optionally be employed together with at leastone topically administrable, in particular inhalative, respiratorytherapeutic, in particular as a combination therapy and/or incomedication. For further details concerning this point, reference maybe made to the above discussions of the other aspects of the invention.

The present invention likewise provides the use of at least onesystemically administrable or administered, in particular oral,monoterpene, preferably 1,8-cineol, for the prophylactic and/or curativetreatment of anti-oxidative and/or anti-inflammatory processes in thehuman body in particular of smokers or for preparing a medicament forthe prophylactic and/or curative treatment of antioxidative and/oranti-inflammatory processes in the human body in particular of smokers.Here, the monoterpene can be employed together with at least onetopically administrable, in particular inhalative, respiratorytherapeutic, in particular as a combination therapy and/or incomedication. For further details concerning this aspect of theinvention, reference may be made to the above discussions of the otheraspects of the invention, which also, correspondingly, apply to thispoint.

Finally, the present invention also provides the use of at least onesystemically administrable, in particular oral, monoterpene, preferably1,8-cineol, for increasing the corticosteroid sensitivity of smokers, inparticular in the prophylactic and/or therapeutic treatment ofrespiratory disorders, in particular bronchopulmonary disorders. Here,the monoterpene can optionally be employed together with at least onetopically administrable, in particular inhalative, respiratorytherapeutic, in particular as combination therapy and/or incomedication. For further details concerning this aspect of sheinvention, reference may be made to the above discussions of the otheraspects of the invention.

Specifically in the treatment of smokers with a systemic or oralmonoterpene, preferably 1,8-cineol, it is possible to control thenicotine-induced effect: this is because oxygen radicals like thoseformed during smoking reduce corticosteroid sensitivity, which ischaracteristically low for example in COPD. An additional therapy forsmokers, in particular those having bronchopulmonary disorders, such asCOPD, with a monoterpene, preferably 1,8-cineol, or else a therapy ofsmokers or former smokers not having respiratory disorders with1,8-cineol surprisingly prevents the development of bronchopulmonarydisorders, such as, for example, COPD, or, in the case of existingrespiratory disorders, reduces exacerbations and a progressive course.Furthermore, specifically 1,8-cineol is also suitable for protectionagainst harmful environmental effects.

Systemic administration of the monoterpene, preferably 1,8-cineol,allows—as discussed below—a significant improvement of pulmonaryfunction, in particular in the context of a combination therapy withinhalative or topical respiratory therapeutics, which can be attributedinter ails, to the anti-inflammatory and/or anti-oxidative action of themonoterpene, preferably 1,8-cineol. The systemic monoterpene, preferably1,8-cineol, inhibits the prooxidative actions of topical corticosteroidsand for its part mediates a non-steroid-like antioxidative action. As aresult, the desired steroid sensitivity is increased, in particular alsoin cases of reduced steroid sensitivity in COPD. Owing to the expositionof the respiratory tract to inhalative noxious substances, in particularcigarette smoke, the positive effects relate mainly to inhalativesteroids.

It is to be understood that, for further details concerning theindividual aspects of the invention, reference may be made to the moredetailed discussions in connection with the first aspect of theinvention, which also, correspondingly, apply to the other aspects ofthe invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the stimulation of the action of the inhalativecorticosteroid beclometasone by the monoterpene 1,8-cineol (10⁻⁶ mol/l)in LPS-stimulated human monocytes in vitro.

FIG. 2 illustrates the effects of 1,8-cineol on the IL1beta inhibitionby beclometasone in vitro.

FIG. 3 illustrates the concentration-dependent modulating effects of1,8-cineol on O₂ ⁻ and NO production in stimulated human monocytes invitro

FIG. 4 illustrates the stimulation of monocyte O₂ ⁻ production with highconcentrations 10⁻² mol/l) of beclometasone.

FIG. 5 illustrates the comparative actions of beclometasone and1,8-cineol regarding the inhibition/stimulation of superoxide (O₂ ⁻).

FIG. 6 illustrates the effect on O₂ ⁻— inhibition provided bybeclometasone (alone), 1,8-cineol (alone) and their combination.

FIG. 7 provides data illustrating that the activity of 1,8-cineol isweakened by the properties of beclometasone.

DETAILED DESCRIPTION OF THE INVENTION

In the context of the present invention, there has been found inparticular the synergistic anti-inflammatory action of monoterpenes andtopical respiratory therapeutics (for example inhalativeglucocorticoids).

Particularly surprisingly, as the basis of the present invention, it hasbeen found that therapeutically relevant concentrations of 1,8-cineolsignificantly increase the anti-inflammatory action of topicalrespiratory therapeutics, in particular topical glucocorticoids, bysynergistic inhibition of the cytokine production. The applicant wasable to demonstrate a synergistic anti-inflammatory action ofmonoterpenes and topical respiratory therapeutics, in particular topicalglucocorticoids. Thus, for example, even low therapeutic concentrationsof 1,8-cineol (for example 10⁻⁶ mol/l) inhibit the production ofIL-1beta significantly compared to subtherapeutic concentrations ofbeclometasone, for which, when used on its own, no significantinhibition could be demonstrated. In contrast, by combining 1,8-cineoland inhalative glucocorticoid (beclometasone), a significant inhibitioncould be demonstrated even for subtherapeutic and therapeuticconcentrations of beclometasone with a resulting more intensive actionof ICS. More detailed clinical studies show that it is possible toreduce the dose of the inhalative ICS by up to 30% to 50% and moreduring a systemic long-term therapy with 1,8-cineol (for exampleSoledum® capsules).

The essential clinical meaning is that the antiinflammatory action ofminimal concentrations, which decrease in the periphery of the lung, ofcommon ICS (metered aerosols and powder preparations) becomes moreintensive. The use of the combination according to the invention ofsystemic monoterpene and topical respiratory therapeutic, in particulartopical glucocorticoid, (for example oral 1,8-cineol and ICS orbeclometasone) is advantageous in particular in the therapy of aperipheral respiratory inflammation in bronchial asthma and COPD as anovel therapeutic concept and for modulating the steroid-refractoryprogression of the pulmonary disorder, to prevent the development ofirreversible respiratory insufficiency. However, of particular clinicalvalue is the therapeutic use of monoterpenes, in particular 1,8-cineol,for the prophylaxis and therapy of early forms of COPD (GOLD 0 or GOLDI), for which there is currently no anti-inflammatory therapyrecommended by all lung associations world-wide.

Furthermore, by a combined therapy of systemic monoterpene and topicalrespiratory therapeutic, in particular topical glucocorticoid (forexample oral 1,8-cineol and ICS or beclometasone), thesteroid-refractory respiratory inflammation caused by cigarette smokeand also other harmful proinflammatory or oxidative environmentalsubstances such as, in particular, ozone (O₃), and the development ofCOPD is inhibited prophylactically and/or therapeutically.

A further essential aspect of the present invention is in particularalso the prophylactic and alleviating effect of monoterpenes, inparticular 1,8-cineol, in combination with topical respiratorytherapeutics, in particular topical glucocorticoids, or else ofmonoterpenes on their own, in particular 1,8-cineol, on inflammations insmokers for the prevention and amelioration of the damage to therespiratory tract caused by cigarette smoke. This damage occurs inparticular even many years after smoking cessation or after the actionof other noxious substances and is characterized clinically by aprogressive obstruction and the development of emphysema withrespiratory insufficiency during ongoing antiobstructive therapy.

Especially using the monoterpene 1,8-cineol as additional therapy withmodern combined therapy forms (for example ICS plus LABA or ICS incombination with vagolytics or else ICS or SABA on their own), inlong-term therapy, surprisingly, in former smokers who had ceasedsmoking more than ten years previously, an inhibition of the productionof TNF-α and an increased production of IL-8 in ex-vivo stimulatedperipheral human monocytes was found compared to normal monocytes ofnon-smokers. From these patients, monocytes were obtained during ongoingtherapy with ICS and incubated in vitro with a topical glucocorticoid ina dose-dependent manner. In particular in comparison with a group ofnormal subjects not undergoing therapy with 1,8-cineol, the resultsshow, with earlier onset, a more pronounced inhibitory action on theproduction of IL-8 and TNF-α in monocytes of patients with COPD. Theseresults lead to the new finding that the inhibition of steroid-sensitivemechanisms alone is not able to have a sufficient effect on the courseof the disease, so that a systemic additional therapy with monoterpenesdecisively improves persistent respiratory inflammation in COPS, helpsto reduce exacerbations in persisting inflammations and in particular inthe periphery intensifies the action of smaller concentrations, relevantfor the respiratory tract, of topical glucocorticoids or otherinhalative respiratory therapeutics.

Currently, the inhibition of exacerbations is one of the most importanttherapeutic aims in smokers and former smokers suffering from COPS whichcan be ameliorated by the non-steroidal effects of the monoterpene1,8-cineol. In addition, 1,8-cineol enhances anti-inflammatory andantiobstructive effects of topical respiratory therapeutics, inparticular topical glucocorticoids, so that even hitherto unknownpharmaceutical combinations of, for example, ICS and 1,8-cineol oranother monoterpene, LABA and 1,8-cineol, SABA and 1,8-cineol and alsoof ICS, SABA and 1,8-cineol or of ICS, LABA and 1,8-cineol are suitableas a therapeutical alternative to the therapy of asthma and COPS of alldegrees of severity and for the additional treatment of the activesystemic component in COPS by the systemic availability of monoterpenes,in particular in capsules which dissolve in the small intestine or aspowders.

In the context of the present invention, in the search for theunderlying property of monoterpenes, in particular 1,8-cineol, whichintensifies anti-inflammatory actions of topical steroids, theapplicant, has additionally found an antioxidative action of 1,8-cineoldue to inhibition of the production of superoxides (O₂ ⁻ radicals), theactivity of superoxide dismutases (SOD) and of hydrogen peroxide (H₂O₂)which as end product of the oxidation stimulates the production ofinflammation mediators, in particular of cytokines and arachidonic acidmetabolises. Here, for the first time, an inhibition of the spontaneousproduction of O₂ ⁻ radicals was demonstrated at therapeuticconcentrations of 1,8-cineol which, at relatively low concentrationsrelevant for respiratory air, stimulates O₂ ⁻ radicals and in thetherapeutic range inhibits the production of O₂ radicals and H₂O₂. Thecause of these antioxidative actions of 1,8-cineol was surprisinglyfound to be 1,8-cineol as active inducer of NO production which, viathis mechanism, removes O₂ ⁻ from the organism as substrate for theformation of NO production. It has thus been found that monoterpenessuch as 1,8-cineol actively induce NO production by mediatingantioxidative effects. Here, for the first time, it was possible todemonstrate modulating effects of 1,8-cineol for controlling oxidative,cell-damaging and proinflammatory effects by inhibition of O₂ ⁻ radicalsand a contrary stimulation of anti-inflammatory and vasodilatory NO inthe therapeutic range of 1,8-cineol. These results are of integralimportance for the prophylaxis and therapy, in particular of pulmonarydisorders associated with cigarette smoking, including pulmonaryemphysema and the regulation of the tone of pulmonary vessels, and alsoof damage to greater and lesser circulation. Thus, an increasedproduction of O₂ ⁻ radicals is mediated by cigarette smoke, infections,nanoparticles, ozone, allergens and other environmental effects whichcan be inhibited permanently by a long-term therapy with 1,8-cineol andmoreover can be utilized advantageously as a substrate for theproduction of NO.

NO is known to be an anti-inflammatory mediator, vasodilator, inhibitorof inflammatory mediators, histamine, granulocyte adhesion and plateletaggregation and also as an activator of ciliary function and mucosalclearance and protects comprehensively against respiratory infectionsand exacerbations of asthma and COPD in all disease stages. In thisrespect, 1,8-cineol is suitable as a continuous therapeutic which, inchronic bronchitis, COPD, emphysema and rhinosinusitis, by modulation,normalizes and adequately adapts to the respective requirements asuppressed NO production by favourable degradation of O₂ ⁻ radicals withinduction of NO. This leads in particular to novel indications for theuse of monoterpenes, in particular 1,8-cineol, preferably in arelatively high, systemically effective daily dose of, for example, from600 to 1200 mg, to regulate organ perfusion and to protect the upper andlower respiratory tracts including the lung against noxious substancesacting as pathogens, in particular cigarette smoke, respiratoryinfections and allergic and non-allergic respiratory inflammation incases of hyperactivity, asthma and rhinitis.

To summarize: the findings discovered in the context of the presentinvention about monoterpenes lead to a completely new understanding ofthe group, previously not recognized by the person skilled in the art,of secretolytics and mucolytics including natural ethereal oils or mixedterpenes, ambroxol and N-acetylcysteine, whose use hitherto servedprimarily to loosen mucus, but not causally to release NO or to modulateother mechanisms and thus not primarily for the prophylaxis and therapyof multifactorial respiratory inflammation. This means that theconventional temporally limited therapy with in most cases ineffectivesubstances targets only actual mucus hypersecretion and that therefore along-term therapy to prevent the development and progression ofrespiratory inflammation in COPD and asthma by early use of effectivesubstances with combined antioxidative and anti-inflammatory activityprofile and a non-steroidal anti-inflammatory mechanism of action forenhancing the activity of topical respiratory therapeutics, inparticular glucocorticoids, and also good compatibility without steroidside-effects in contrast to the general guidelines of national andinternational lung associations should be proposed as a matter ofurgency. Here, effective substances, such as monoterpenes, in particular1,8-cineol, may play a more central role in the future owing to theirbetter availability in the respiratory tract as a consequence of theirhigh lipophilicity and the exhalation of the active compound afteralveolar uptake from the bloodstream into the pulmonary periphery.Therefore, for monoterpenes, in particular 1,8-cineol, a newclassification as belonging to a novel group of substances as“Non-Steroidal Airway Inflammation Modifier (NSAIM)” should be proposed.

Further embodiments, adaptations and variations and also advantages ofthe present invention are readily discernible and feasible for theperson skilled in the art on reading the description, without the personleaving the scope of the present invention. The following workingexamples serve only to illustrate the present invention, without theinvention being limited thereto.

WORKING EXAMPLES Example 1 In-Vitro Studies

In in vitro studies, it was found that monoterpenes (here specifically:1,8-cineol) are capable of enhancing the activity of inhalativerespiratory therapeutics, in particular glucocorticoids (herespecifically: beclometasone), in a significant, in particularsynergistic, manner.

Surprisingly, it has been found that therapeutically relevantconcentrations of 1,8-cineol significantly enhance the anti-inflammatoryaction of topical glucocorticoids by synergistic inhibition of cytokineproduction (see Table 1).

Table 1 shows the synergistic activity of 1,8-cineol (10⁻⁶ mol/l) andbeclometasone on the LPS-stimulated production of IL-1beta in humanmonocytes in vitro. Monocyte IL-1beta production (n=14-15, 4experiments) in monocytes is inhibited significantly by cineol (10⁻⁶mol/l) compared to the control. Cineol and beclometasone synergisticallyinhibit IL-1beta production more than beclometasone on its own. Comparedto cineol (10⁻⁶ mol/l) on its own, the IL-1beta production is alsoinhibited synergistically and to a significantly more pronounced degreeby addition of beclometasone (p<0.05).

TABLE 1 Synergistic action of 1,8-cineol (10⁻⁶ mol/l) and beclometasone(“becl.”) on the LPS-stimulated production of IL-lbeta in humanmonocytes in vitro Effect vs. cineol IL-lbeta Effect vs. control 10⁻⁶mol/l pg/5 × Inhibition Inhibition mol/l 10⁴ cells (%) p Value (%) pValue control 5252 ± 1017  0 ± 19 — — — cineol 10⁻⁶ 3548 ± 600  32.4 ±17   0.0100  0 ± 17 — beclometasone 10⁻¹² 5246 ± 1028 0.1 ± 19  0.9634(+47.8 ± 19)     0.0100 beclometasone 10⁻¹¹ 4217 ± 864  19.7 ± 20  0.0596 (+18.9 ± 20)     0.5557 beclometasone 10⁻¹⁰ 4047 ± 940  22.9 ±23   0.0661 (+14 ± 23)   0.6945 beclometasone 10⁻⁹ 2654 ± 545  49.4 ±20   0.0449 25.2 ± 20   0.0790 cineol 10⁻⁶ + becl. 10⁻¹² 3966 ± 642 24.5 ± 16   0.1904 (+11.8 ± 16)     0.0401 cineol 10⁻⁶ + becl. 10⁻¹¹2632 ± 474  49.9 ± 18   0.0100 25.8 ± 18   0.0538 cineol 10⁻⁶ + becl.10⁻¹⁰ 2696 ± 607  48.7 ± 22   0.0088 24 ± 22 0.0443 cineol 10⁻⁶ + becl.10⁻⁹ 347 ± 56  93.4 ± 16   0.0049 90.2 ± 1.6  0.0287

The monocyte IL-1beta production (n=14-15, 4 experiments) in monocytesis inhibited significantly by 1,8-cineol (10⁻⁶ mol/l) compared to thecontrol. 1,8-Cineol and beclometasone synergistically inhibit theIL-1beta production, more strongly than beclometasone on its own.Compared so cineol (10 mol/l), the IL-1beta production is also inhibitedsynergistically and to a significantly more pronounced degree byaddition of beclometasone (p<0.05).

The results from human monocyte cultures show for the first time thatthe LPS-stimulased production of IL1beta is inhibited to a significantlymore pronounced degree (p<0.01) by beclometasone and 1,8-cineol 10⁻⁶mol/l (73.4±19%) tahn by beclometasone on its own (49.9±20%) or1,8-cineol on its own (32.4±17%) (see FIGS. 1 and 2). This is the firstdemonstration of a synergistic anti-inflammatory action of systemicmonoterpenes and topical glucocorticoids.

In this context, FIG. 1 shows the stimulation of the action of theinhalative corticosteroid beclometasone by the monoterpene 1,8-cineol(10⁻⁶ mol/l) in LPS-stimulated human monocytes in vitro; the additioneven of small amounts of 1,8-cineol effects a significant increase ofthe activity of beclometasone, associated with an increased inhibitionof IL-1beta. FIG. 1 shows the synergistic action of 1,8-cineol andbeclometasone: for 20 hours, monocytes (n=14-15, 4 experiments) ofhealthy subjects (10⁵/ml) were incubated with 1,8-cineol (10⁻⁶mol/l=0.015 μg/ml) and beclometasone (10⁻¹²-10⁻⁹ mol/l) in the presenceof LPS (10 mg/ml). In cell culture supernatants, the production ofIL-1beta was determined by ELISA (from Cayman, AnnArbor, Mich., USA).1,8-Cineol on its own (−32%±17%, p=0.01) and therapeutically relevantconcentrations of beclometasone (10⁻⁹ mol/l, p=0.045) inhibit theproduction of IL-1beta. In contrast, the LPS-stimulated production isinhibited to a significantly more pronounced degree (p<0.031) by acombination of 1,8-cineol (10⁻⁶ mol/l) plus beclometasone (10⁻¹¹-10⁻⁹mol/l) than by beclometasone on its own. 1,8-Cineol intensifies inparticular the action of subtherapeutic concentrations of beclometasonewhich are relevant for the peripheral respiratory tract.

FIG. 2 shows the effects of 1,8-cineol on the IL-1beta inhibition bybeclometasone in vitro. FIG. 2 likewise illustrates the synergisticaction of 1,8-cineol and beclometasone at higher therapeuticconcentrations: the LPS-stimulated production of IL1-beta (n=14-15, 4experiments) is inhibited by therapeutically relevant concentrations of1,8-cineol in a dose-dependent manner and significantly (p<0.01)compared to the LPS control. The activity of therapeutically relevantconcentrations of beclometasone is inhibited significantly (p<0.01) morestrongly by 1,8-cineol compared to beclometasone plus 1,8-cineol. Toachieve this activity, concentrations of the two substances which are atleast 10 times higher have to be present.

Furthermore, the results allow it to be demonstrated for the first timethat even low therapeutic concentrations of 1,8-cineol (10⁻⁶ mol/l)significantly inhibit the production of IL-1beta compared tosubtherapeutic concentrations of beclometasone (beclometasone: 10¹²mol/l: 0%; 10⁻¹¹ mol/l: −19.7%±20%; 10⁻¹⁰ mol/l: −22.9%±13%) for whichno significant inhibition was shown.

In contrast, by combining 1,8-cineol and beclometasone a significantinhibition could be demonstrated even for subtherapeutic and therapeuticconcentrations of beclometasone with a resulting increase in the actionof ICS.

These findings confirm the clinical data given below with respect to asignificant reduction of the inhalative ICS dose of up to 60% duringlong-term therapy with oral 1,8-cineol (Soledum® capsules).

A further essential novel aspect of the present data is the prophylacticand alleviating effect of 1,8-cineol in combination with topicalglucocorticosteroids or else by 1,8-cineol on its own on inflammationsin smokers for the prevention and amelioration of the damage to therespiratory tract caused by cigarette smoke. This damage occurs inparticular even many years after smoking cessation or after the actionof other noxious substances and is characterized clinically by aprogressive obstruction and the development of emphysema withrespiratory insufficiency during ongoing antiobstructive therapy. Withrespect to the recommended combined standard therapies of long-actingbeta-2-sympathomimetics (LABA), short-acting beta-2-sympathomimetics(SABA) and inhalative steroids (ICS), novel, hitherto unknown optionsfor additional therapy with 1,8-cineol result, with the aim of enhancingeffects of topical therapy and to treat a respiratory disorder nowidentified as a systemic disorder in a combined manner topically andsystemically with additional intensification of the topicalanti-inflammatory and bronchodilatory therapy as systemic disorder bylong-term therapy.

Currently, the inhibition of exacerbations is one of the most importanttherapeutic targets for smokers and former smokers with COPD which canbe ameliorated by the non-steroidal effects of the monoterpene1,8-cineol in addition, 1,8-cineol improves anti-inflammatory andantiobstructive effects of ICS plus LABA, so that hitherto unknownpharmaceutical combination products or kiss consisting, for example, ofICS+1,8-cineol or another monoterpene, LABA+1,8-cineol, SABA+1,8-cineolor else ICS+SABA+1,8-cineol or ICS+LABA+1,8-cineol, and also moderncombinations with long-acting vagolytics will be suitable in the futureas a therapeutic alternative for the therapy of asthma and COPD in alldegrees of severity and for the additional treatment of the activesystemic component in COPD owing to the systemic availability ofmonoterpenes in the form of capsules which dissolve in the smallintestine or as powders.

In the context of the present invention, for the first time, modulatingantioxidative and anti-inflammatory effects of monoterpenes (1,8-cineol)could be demonstrated for controlling oxidative processes and for theinduction of nitric oxide production (NO production) in the search forthe underlying property of monoterpenes, in particular 1,8-cineol, forthe intensification of anti-inflammatory actions of topical steroids, anantioxidative action of 1,8-cineol owing to inhibition of the productionof superoxides (O₂ ⁻ radicals), the activity of superoxide dismutases(SOD) and of hydrogen peroxide (H₂O₂) has been found. Here, for thefirst time, an inhibition of the spontaneous and stimulated productionof superoxides (O₂ ⁻ radicals) was demonstrated at therapeuticconcentrations of 1,8-cineol, so that the provision of the substrate forthe dismutation of O₂ ⁻ radicals via a superoxide dismutase activitypartially inhibited by 1,8-cineol also inhibited the production of O₂ ⁻radicals and H₂O₂ even at low concentrations relevant for therespiratory air and in the therapeutic range. The essential cause ofthese anti-oxidative actions of 1,8-cineol was surprisingly found to be1,8-cineol as active inducer of NO production which, via this additionalmechanism, removes O₂ ⁻ from the organism as substrate for the formationof NO production. It has thus been found that monoterpenes such as1,8-cineol actively induce NO production by mediating antioxidativeeffects. (see Table 2).

Table 2 shows the effect of 1,8-cineol on the PMA-stimulated superoxideproduction (O₂ ⁻ production) (in RPMI 1640) of normal human monocytes invitro. The dose-dependent effects of 1,8-cineol (4 experiments, n=9-14)on the O₂ ⁻ production were measured by determining INT-formazan inculture supernatants (RPMI 1640) of human monocytes (10⁵/ml) after 20hours. The O₂ ⁻ production was not stimulated by PHA (500 mmol/l). Forstatistical analysis, the non-parametric Mann & Whitney test was used(p<0.05).

Here, for the first time, it was possible to demonstrate modulatingeffects of 1,8-cineol for controlling oxidative, cell-damaging andproinflammatory effects by inhibition of O₂ ⁻ radicals and a contrarystimulation of anti-inflammatory and vasodilatory NO in the therapeuticrange of 1,8-cineol (see FIG. 3).

TABLE 2 Effect of 1,8-cineol on the PMA-stimulated superoxide production(O₂ ⁻ production) in RPMI 1640 normal human monocytes in vitro INT-Comparison 1,8-Cineol formazan with control μg/ml (mol/l) (nmol/10⁵) (%)p Value spontaneous 4828 ± 251 — — PMA 4203 ± 267 −12.9 ± 6   0.09900.0015 (10⁻⁸) 5.364 ± 229  +27.6 ± 4   0.0083 0.015 (10⁻⁷) 5235 ± 341+24.5 ± 6   0.0327 0.15 (10⁻⁶) 5327 ± 360 +26.7 ± 7   0.0378 0.3 (2 ×10⁻⁶) 5540 ± 359 +31.8 ± 6   0.0091 0.6 (4 × 10⁻⁶) 6045 ± 534 +43.8 ±9   0.0277 0.9 (6 × 10⁻⁶) 6107 ± 437 +45.3 ± 7   0.0050 1.2 (8 × 10⁻⁶)4099 ± 234 −2.5 ± 6   0.7721 1.5 (10⁻⁵) 2438 ± 389 −42 ± 16 0.0024 3 (2× 10⁻⁵)  634 ± 139 −84.9 ± 22   <0.0001

FIG. 3 shows the concentration-dependent modulating effects of1,8-cineol on O₂ ⁻ NO production in stimulated human monocytes in vitro:Following stimulation (20 hours) of normal human monocytes (10⁵/ml), theproduction of NO is induced and that of O₂ ⁻ is suppressed in thecontrol (i.e. without 1,8-cineol). In contrast, low concentrations of1,8-cineol slightly induce O₂ ⁻ production and, at subtherapeuticconcentrations (0.15 μg/ml=10⁻⁶ mol/l), inhibit the production of NO. Inthe therapeutic range of 1,8-cineol, the O₂ ⁻ production is inhibitedstrongly in the presence of stimulating effects on the production of NO(*p<0.04, **p<0.01).

These results are of integral importance for the prophylaxis andtherapy, in particular, of pulmonary disorders associated with cigarettesmoking, including pulmonary emphysema and the regulation of the tone ofpulmonary vessels, and also of damage to greater and lesser circulation.Thus, an increased production of O₂ ⁻ radicals is mediated by cigarettesmoke, infections, nanoparticles, ozone, allergens and otherenvironmental effects, which production can be inhibited permanently bya long-term therapy with 1,8-cineol and moreover can be utilizedadvantageously as a substrate for the production of NO. NO is known tobe an anti-inflammatory mediator, vasodilator, inhibitor of inflammatorymediators, histamine, granulocyte adhesion and platelet aggregation andalso as an activator of ciliary function and mucosal clearance andprotects comprehensively against respiratory infections andexacerbations of asthma and COPD in all disease stages. In this respect,1,8-cineol is suitable as a continuous therapeutic which, in chronicbronchitis, COPD, emphysema and rhinosinusitis, by modulation,normalizes and adequately adapts to the respective requirements asuppressed NO production by favourable degradation of O₂ ⁻ radicals withinduction of NO. This leads in particular to novel indications for theuse of monoterpenes, in particular 1,8-cineol, preferably in arelatively high, systemically effective daily dose, to regulate organperfusion and to protect the upper and lower respiratory tractsincluding the lung against noxious substances acting as pathogens, inparticular cigarette smoke and other emissions or fine dusts,respiratory infections and allergic and non-allergic respiratoryinflammations in cases of hyperactivity, asthma and rhinitis. Thesehitherto unknown properties associated with the action of monoterpenes,in particular 1,8-cineol, may contribute in establishing in the future,for the first time, the additional therapy with 1,8-cineol in theliterature and the therapy guidelines.

Example 2 Clinical Results

10 patients 56 to 72 years of age with persistent bronchial asthma (GINAII) treated with a combination therapy of inhalative glucocorticoid(beclometasone, 2×200 μg/die by inhalation) and inhalative long-actingbeta-2-sympathomimetics (LABA, salmeterol) and also oral theophyllinwere given 1,8-cineol (Soledum® capsules) 4×200 mg/die orally for oneweek. Even after a one-week therapy at the dose mentioned above, in 8 ofthe 10 subjects a slight to moderate improvement of lung function wasachieved. After continuing therapy for a further twelve weeks, thepersistent bronchial asthma had stabilized to such an extent that in 7of the 10 patients the inhalative glucocorticoid required could bereduced by up to 60% and in 2 of the 10 patients the inhalativeglucocorticoids could be discontinued altogether at times. The therapywas tolerated well, without any side-effects. In 5 of the patientstreated, the betamimetics required, too, could be reduced by up to 40%.

A further 12 patients 59 to 78 years of age with persistent bronchialasthma (GINA TIT) treated with a combination therapy of inhalativeglucocorticoid (beclometasone, 2×400 μg/die by inhalation) andinhalative long-acting beta-2-sympathomimetics (LABA, salmeterol) andalso oral theophyllin were given 1,8-cineol (Soledum® capsules) 4×200mg/die orally for one week. Even after a one-week therapy at the dosementioned above, in 9 of the 12 subjects a slight to moderateimprovement of lung function was achieved. After continuing therapy fora further twelve weeks, the persistent bronchial asthma had stabilizedto such an extent that in 9 of the 12 patients the inhalativeglucocorticoid required could be reduced by up to 30%. The therapy wastolerated well, without any side-effects. In 4 of the patients treated,the betamimetics required, too, could be reduced by up to 25%.

The results of the experiments show that monoterpenes significantlyincrease the efficacy of inhalative respiratory therapeutics, and thatit is therefore possible to significantly reduce the amounts thereofwhich must be administered.

Example 3 Further Clinical Results

In a placebo-controlled double-blind study, the effect of an additionaltherapy with 1,8-cineol in the form of capsules which dissolve in thesmall intestine (Soledum® capsules, 3×200 mg/die oral) on exacerbationrate and lung function was examined in 3 winter months of two successiveyears using 242 smokers with COPD (GOLD II to III). Both patient groupswere identical with respect to age, sex, body mass index, smoker status,lung function and a guideline-conform medication of ICS, LABA, SABA,anticholinergics and theophyllin. In the verum group, the additional,therapy with 1,8-cineol led to a significant reduction in theexacerbation rate of −38.5% compared to the placebo group. Additionally,the lung function (FEV1) in the verum group (+5.1%) had improvedsignificantly compared to the placebo group (−1%). Clinical parameterssuch as the St. George's Respiratory Questionnaire (SGRQ), too, hadimproved significantly more in the verum group (−10.4 units) compared tothe placebo group (−5 units). Thus, the results show, for the firsttime, that an additional therapy with 1,8-cineol in the form of capsuleswhich dissolve in the small intestine reduces the decrease, reported inthe literature, in the frequency of exacerbations by the known combinedtherapeutic approaches involving budesonide and formoterol (−24%, 13)and fluticasone and salmeterol (−25%, 14) by a further

Summary and Outlook:

The findings reported above confirm a significant reduction of theinhalative ICS dose of up to 60% during a long-term therapy with oral1,8-cineol (Soledum® capsules). The essential clinical significance isthe intensification of the anti-inflammatory action of minimalconcentrations of customary ICS (for example metered aerosoles andpowder preparations) which decrease in the periphery of the lung.

The use of 1,8-cineol and ICS is advantageous in particular in thetherapy of a peripheral, respiratory inflammation in COPD as a noveltherapeutic concept and for modulating the steroid-refractoryprogression of the pulmonary disorder, to prevent the development ofirreversible respiratory insufficiency. Of particular clinical value is,for example, the therapeutic use of 1,8-cineol for the prophylaxis andtherapy of early forms of COPD (i.e. GOLD 0 or GOLD I), for which thereis currently no anti-inflammatory therapy recommended by all lungassociations world-wide. Moreover, by a combined therapy of 1,8-cineoland ICS, the steroid-refractory respiratory inflammation caused bycigarette smoke and also other harmful proinflammatory and oxidativeenvironmental substances such as, in particular, ozone (O₃), and thedevelopment of COPD is inhibited prophylactically and/ortherapeutically.

Example 4 Further Tests and Test Data

More detailed in vitro studies of the anti-inflammatory action of1,8-cineol, in particular in acute colds and/or chronic-obstructiverespiratory disorders

In vitro studies to determine the effects of an additional therapy with1,8-cineol and inhaled steroids (ICS) on the production of superoxides(O₂ ⁻) in normal human monocytes

Introduction

According to the current state of research, the applicant was able todemonstrate antioxidative actions of the active compound 1,8-cineol, inaddition to anti-inflammatory actions. The antioxidative action is basedprimarily on an inhibition of superoxides and an additional action byinhibition of the superoxide dismutase activity (SOD activity),accompanied by a resulting inhibition of hydroperoxides (H₂O₂) which actin a proinflammatory manner on the transcription, with formation ofcytokines and other inflammation mediators.

Systemic 1,8-cineol, for example in the form of Soledum® capsules, canbe employed—as discussed above—for example as additional therapy firstlyfor severe COPD (for example GOLD III/IV) and/or as monotherapy for mildforms (for example GOLD I/II), i.e. also for chronic and acutebronchitis. It appears to be particularly worthy of mention that, forchronic bronchitis, the COPD guideline (GOLD) does not suggest anyanti-inflammatory or antioxidative therapy apart from avoidance ofnoxious substances. This constitutes a gap in the current guidelineswhich was closed in the context of the present application.

In the more detailed studies of the applicant on 1,8-cineol, it waspossible to verify in principle the hypothesis that an additionaltherapy with systemic 1,8-cineol in correlation with earlier and ongoingclinical studies with Soledum® capsules can mediate a potentiatingsuperior antioxidative and/or anti-inflammatory action by enhancing themediator inhibition in normal human monocytes.

Since an antioxidative effect of the standard therapy of severe COPDconsisting of, for example, LABA plus ICS has hitherto not been known,these newly recognized effects of 1,8-cineol on the inhibition ofsuperoxides compared to ICS and LABA (1,8-cineol vs. ICS and 1,8-cineolplus ICS) have been examined for the first time in the context of thepresent invention.

Hypothesis and Issues

Firstly, it was an object to examine the antioxidative effects of anadditional therapy with 1,8-cineol for inflammatory respiratorydisorders (for example COPD or asthma). Since the action of 1,8-cineolas comedication, in particular in combination with inhalative steroidsand other guideline recommendations, has hitherto not been known, thereis a need to develop novel principles to justify the novel therapeuticapproach of using 1,8-cineol for respiratory disorders. Based on thisknowledge it is an object to justify the present results or the clinicalstudies and to establish the strategy of the additional therapy by a newunderstanding. This is also the base for the examination of novelclinical issues concerning the use of 1,8-cineol.

The additional effect of 1,8-cineol (4×10⁻⁶ mol/l and 6×10⁻⁶ mmol/l) isto be tested by co-incubation with therapeutically relevantconcentrations (10 mol/l, 10⁻¹⁰ mol/l, 10⁻⁹ mol/l) and higherconcentrations (10⁻⁸ mol/l, 10⁻⁷ mol/l, 10⁻⁶ mol/l) of beclometasone(“becl.”). Moreover, the effects of beclometasone on its own at theconcentrations mentioned is to be deter mined in comparison to1,8-cineol. It is intended to test these effects on a combination of1,8-cineol and beclometasone (“becl.”) as standard-ICS on the FCS (fetalcalf serum)-stimulated production of O₂ ⁻ on normal human monocytes. Theaim of the studies is to test additional effects of suboptimal (4×10⁻⁶mol/l) and optimal (4×10⁸⁶ mol/l) concentrations of 1,8-cineol ondifferent concentrations of beclometasone.

Methods

In Vitro Method for Determining the Additional Effects of aCo-Incubation of 1,8-cineol and Beclometasone

As already described, monocytes were isolated from 50 ml of venous bloodwhich was repeatedly donated voluntarily for the experiments by healthynon-smoking subjects (n=4). The active compounds beclometasone and1,8-cineol were diluted with ethanol up to a maximum concentration of0.01%. The substances were incubated individually (beclometasone 10⁻¹²to 10⁻⁶ mol/l) and in combination (10⁻¹¹ to 10⁻⁹ mol/l beclometasonewith 6×10⁻⁶ mol/l=0.9 μg/ml 1,8-cineol) and also in an additional seriesat a 1,8-cineol concentration which is not antioxidatively active(4×10⁻⁶ mol/l). To this end, the active compounds were incubatedtogether with freshly isolated monocytes (10⁵/ml) and the FCS stimulus(10%, from Sigma) for 20 hours in a cell culture medium (RPMI-1640, fromSigma). The culture supernatants were then obtained after treatment ofthe cell membranes with Triton-X 100 and immediately examined forproduction of O₂ ⁻ radicals.

Analytic Method for the Determination of Superoxides (O₂ ⁻) in CultureSupernatants of Human Monocytes

The determination of the cytosolic superoxide production is based on thereduction of the dye p-iodonitrotetrazolium violet (INTV), which reactsspecifically with superoxide ions, to iodonitrotetrazolium formazan(formazan). INTV is taken up by the cells into the cytosol.Intracellularly, the nitrogen cycle of the INTV is reduced by freesuperoxide radicals, giving rise to a water-soluble intermediate and thewater-soluble formazan, which have their absorption maxima at 505 and490 nm, respectively. In contrast, INTV does not absorb light of thesewavelengths. At the end of an experiment, the cell lysate is (aftertreatment with hydrochloric acid) measured at 492 nm in a photometer.Here, the absorption of light is proportional to the amount ofintracellularly accumulated INT-formazan which can then be determinedusing a formazan calibration curve. The INT-formazan accumulation forits part is determined as a measure for the intracellular production ofsuperoxide.

Crossreactions with 1,8-cineol

To make sure that true inhibitory effects of 1,8-cineol on theINT-formazan accumulation were present, possible crossreactions of1,8-cineol with the components of the measurement system were excluded.To this end, beclometasone 10⁻⁶ mol/l, 1,8-cineol 10⁻⁵ mol/l, INTV 0.5mg/ml and also beclometasone 10⁻⁶ mol/l+1,8-cineol 10⁻⁵ mol/l+INTV 0.5mg/ml were incubated without cells and the INT-formazan production wasmeasured. Neither 1,8-cineol nor beclometasone on their own or incombination with INTV had any detectable effect on the determination ofthe INT-formazan production. Crossreactions of 1,8-cineol andbeclometasone with the measurement method could therefore be excluded.

Statistical Analyses

Studies on the dose-dependent production of O₂ ⁻ radicals in the variousissues were carried out in key experiments with beclometasone (Expt, 3,n=10 to 11), 1,8-cineol (Expt. 5, n=12), beclometasone+1,8-cineol 4×10⁻⁶mol/l (Expt. 4, n=14 to 15) and beclometasone H-1,8-cineol 6×10⁻⁶ mol/l(Expt. 3, n=11 to 12). Effects of 1,8-cineol and beclometasone areexpressed as “% of the FCS control” and were examined statisticallyusing the non-parametric Mann & Whitney test. p values <0.05 areconsidered to be statistically significant.

Results

Comparison of the Effects of Beclometasone and 1,8-cineol on the FetalCalf Serum (FCS)-Stimulated Production of Superoxides (O₂ ⁻) in NormalHuman Monocytes

Monocytes (10⁵/ml) were incubated with different concentrations ofbeclometasone (10⁻¹² to 10⁻⁶ mol/l, n=10-11) for 20 hours together withthe FCC stimulus (10%). A borderline significant inhibition (−10.5±5%,p=0.0910) of the O₂ ⁻ production was demonstrated only for beclometasone10⁻⁹ mol/l (see Table 3). High concentrations (≧10⁻⁸ mol/l) ofbeclometasone stimulated the monocyte O₂ ⁻ production, with asignificant increase (15.2±2.5%, p=0.0092) at 10⁻⁶ mol/l (see FIG. 4).Thus, an inhibition of the O₂ ⁻ production could not be demonstrated forbeclometasone.

In contrast to the action of beclometasone, a strong inhibition of theO₂ ⁻ production (−42.6±8%, p=0.0007) was demonstrated for 1,8-cineoleven at a therapeutically relevant concentration (0.9 mg/ml=6×10⁻⁶mol/l). In contrast to beclometasone, which at therapeuticconcentrations does not inhibit the O₂ ⁻ production and at higherconcentrations stimulates the O₂ ⁻ production, 1,8-cineol inhibited theO₂ ⁻ production in the therapeutic range. The inhibition profile ofthese different actions of the substances is shown in a comparativemanner in FIG. 5

Effect of a Suboptimal Concentration 0.6 μg/ml) of1,8-cineol+beclometasone on the FCC-Stimulated Production of Superoxides(O₂ ⁻) in Normal Monocytes

Owing to the different activity profiles found for beclometasone and1,8-cineol, additive or synergistic actions of the two substances wereinvestigated. Co-incubations even of a concentration of 1,8-cineol whichis itself not yet oxidatively active with beclometasone (n=14-15) wereinitiated under the experimental conditions described to examine apossible synergistic action of the two substances. The chosenconcentration of 1,8-cineol 4×10⁻⁶ mol/l on its own showed no effect(−9±6%, p=0.2717), and neither did the concentrations of beclometasoneexamined 10⁻¹¹ to 10⁻⁹ mol/l (see Table 5). In contrast to the notsignificantly inhibiting properties of the individual substances, alikewise not significant borderline increase of the O₂ ⁻ production wasdemonstrated for 1,8-cineol+beclometasone 10⁻¹⁰ mol/l (2±7%, p=0.7557)and for 1,8-cineol+beclometasone 10⁻⁹ mol/l (4±8%, p=0.8519).

TABLE 3 Effect of beclometasone (becl.) on the FCS- stimulatedsuperoxide production of normal human monocytes in vitro O₂ ⁻ Percentmol/l n (nmol/ml of control p-Value spontaneous 11  8875 ± 429 — — FCS10% 11 15858 ± 550 — <0.0001 10⁻¹² 11 15050 ± 455 −5.1 ± 3   0.178310⁻¹¹ 11 15042 ± 568 −5.1 ± 3   0.2643 10⁻¹⁰ 10 14702 ± 682 −7.3 ± 5  0.1392 10⁻⁹ 10 14192 ± 733 −10.5 ± 5   0.0910 10⁻⁸ 10 16035 ± 639 −1.1 ±4   0.7513 10⁻⁷ 10 16782 ± 678 +5.8 ± 4   0.2751 10⁻⁶ 10 18240 ± 463 +15 ± 2.5 0.0092

TABLE 4 Effect of 1,8-cineol on the FCS-stimulated superoxide (O₂ ⁻ )production of normal human monocytes in vitro 1,8-Cineol Comparisonmg/ml INT-Formazan to control (mol/l) ( nmol/10⁵) (%) p-Valuespontaneous 13756 ± 1675 — — FCS 10% 21507 ± 1675 56.3 ± 8   0.00220.000015 (10⁻¹⁰) 21360 ± 1766 −0.7 ± 8     0.9081 0.00015 (10⁻⁹) 21329 ±1920 −0.8 ± 9     0.7728 0.0015 (10⁻⁸) 21946 ± 1858 2 ± 8 0.7508 0.015(10⁻⁷) 21899 ± 1879 1.8 ± 8   0.087 0.15 (10⁻⁶) 22286 ± 2036 3.6 ± 9  0.4884 0.3 (2 × 10⁻⁶) 21499 ± 1959 0.04 ± 9   0.9081 0.6 (4 × 10⁻⁶)17240 ± 1637 −19.8 ± 9     0.0833 0.9 (6 × 10⁻⁶) 12341 ± 1061 −42.6 ±8     0.0007 1.2 (8 × 10⁻⁶) 10086 ± 701  −53.1 ± 7     <0.0001 1.5(10⁻⁵) 10202 ± 915  −52.6 ± 9     <0.0001Effect of an Optimum Concentration (0.9 μg/ml) of 1,8-cineolBeclometasone on the FCS-Stimulated Production of Superoxides (O₂ ²⁻) inNormal Monocytes

A therapeutically relevant borderline concentration of 1,8-cineol 6×10©mol/l (0.9 mg/ml) was determined as lowest antioxidatively activeconcentration for 1,8-cineol, and this concentration inhibited the O₂ ⁻production significantly (−50.2±5%, <0.0001). In this experimentalseries, too, beclometasone 10⁻¹¹ to 10⁻⁹ mol/l on its own had nodetectable effect on the O₂ ⁻ production (see Table 6). Co-incubation of1,8-cineol+beclometasone 10⁻¹¹ mol/l inhibited the O₂ ⁻ production(−49.9±5%, p<0.0001), and this effect is comparable (p=0.9215) to theeffect of 1,8-cineol on its own. With increasing concentration ofbeclometasone (10⁻⁹ mol/l) in the presence of 1,8-cineol, theantioxidative action tends to decrease, reaching −38.1±3% (p<0.0001)(see FIG. 6). Statistical analyses show that the inhibition of the O₂ ⁻production by 1,8-cineol+beclometasone 10⁻¹¹ mol/l (−40.9±3%) issignificantly weaker (p<0.0001) compared to 1,8-cineol on its own. Thesame also applies to 1,8-cineol+beclometasone 10⁻⁹ mol/l. Also, comparedto 1,8-cineol+beclometasone 10⁻¹¹ mol/l, the slightly decreasinginhibition of the O₂ ⁻ production in the presence of higher doses ofbeclometasone for 1,8-cineol+beclometasone 10⁻¹° mol/l (p=0.0165) and1,8-cineol+beclometasone 10⁻⁹ mol/l (p=0.0053) is significant. Thesedata show that the activity of 1,8-cineol is weakened by the propertiesof beclometasone (10⁻¹⁰ and 10⁻⁹ mol/l) and that in the combination withbeclometasone the leading role of the antioxidative activity is mediatedby 1,8-cineol—without 1,8-cineol it cannot be detected in thiscombination (see FIG. 7).

TABLE 5 Effect of 1,8-cineol (0.6 μg/ml) and beclometasone (“becl.”) onthe FCS-stimulated superoxide production of normal human monocytes invitro O₂ ⁻ Percent mol/l n (nmol/ml) of control p-Value spontaneous 159294 ± 511 — — FCS 10% 15 17843 ± 940  — <0.0001 1,8-cineol 15 16323 ±1069 −9 ± 6 0.2717 4 x 10⁻⁶ becl. 10⁻¹¹ 14 16562 ± 1081 −7 ± 6 0.4581becl. 10⁻¹⁰ 15 16445 ± 903  −8 ± 5 0.2998 becl. 10⁻⁹ 15 16052 ± 969  −10± 6  0.1466 1,8-cineol + 15 16867 ± 1399 −5 ± 8 0.4186 becl. 10⁻¹¹1,8-cineol + 15 18190 ± 1345 +2 ± 7 0.7557 becl. 10⁻¹⁰ 1,8-cineol + 1518659 ± 1555 +4 ± 8 0.8519 becl. 10⁻⁹

Summary

The present results of the study show that a frequently employedinhalative steroid such as beclometasone does not inhibit and at a nolonger therapeutically relevant high concentration (10⁻⁶ mol/l) evensignificantly increases the stimulated production of O₂ ⁻ radicals inmonocytes. In contrast, the production of O₂ ⁻ radicals is inhibited bytherapeutically relevant concentrations of 1,8-cineol by about 50%.Accordingly, for the first time, the present study now shows that thestrong inhibition of the production of O₂ ⁻ radicals by therapeuticconcentrations of 1,8-cineol in combination with beclometasone can bedemonstrated and provides an advantage which cannot be mediated in anisolated manner by the inhalative steroid alone. This is not a purelyadditive effect but the mediation of the effect of 1,8-cineol on thecombination of 1,8-cineol and beclometasone, without it being possibleto detect an independent antioxidative effect of beclometasone.

The lack of any indication of an inhibition of she formation of O₂ ⁻radicals by beclometasone is presumably indicative of the stimulation ofO₂ radicals found for higher, not therapeutically relevantconcentrations of beclometasone. The results show that there is aninteraction between beclometasone and 1,8-cineol which, at high doses ofbeclometasone, decreases the potent action of 1,8-cineol in anegative-synergistic manner. This is evidenced by the fact that1,8-cineol on its own has a significantly stronger antioxidative actionthan in combination with beclometasone, and that even the activity of1,8-cineol+beclometasone decreases significantly at increasingconcentrations of beclometasone compared to a combination with a smallerbeclometasone concentration.

Besides, further investigations show that fluticasone, too, induces theproduction of O₂ ⁻ radicals, and that this takes place via an inhibitionof superoxide dismutase, which metabolizes O₂ ⁻ to H₂O₂. These effectsalso increase with increasing steroid receptor binding capability, andthe present studies therefore suggest that inhaled steroids are at leastnot capable of developing any antioxidative action via the inhibition ofO₂ ⁻ radicals and very likely do not at all act as antioxidants. As faras this is concerned, the investigations show that 1,8-cineol, at leastwith respect to its surprising superior antioxidative action comparedwith the steroids used to date, mediates an advantageous, hithertounderestimated activity profile in the respiratory tract.

This alone is the reason for the additional therapy with 1,8-cineol ofinflammatory respiratory disorders and makes a long-term therapyparticularly recommendable. Since the development of COPS treated withICS is delayed owing to a reduction of exacerbations, but stillprogresses when treated with a combined therapy, the lack ofantioxidative activity in the medication currently available may play anessential role here. The progression of COPS is accelerated inparticular by smoking cigarettes, which leads to a high deposition ofinhaled O₂ ⁻ radicals in the respiratory tract, which radicals canobviously not be inactivated by ICS or a combined therapy with LABA plusICS, or the therapy is not sufficiently protectively active with respectto epithelial cells of the respiratory tract and macrophages, and it istherefore conceivable that the pathogenic stimulus persists andcontributes to the Progression of the respiratory disorder.

Another novel, aspect of the present invention is the systemicinflammation, hitherto underestimated, in COPS, which inflammation isinduced by smoking cigarettes, but also by the severity of the disorder.As far as this is concerned, the inhalative local therapy is presumablynot sufficient to actually control the course of COPS. Likewise, thepresent data may also explain the lack of any effects of a systemictherapy of COPT) with prednisolone which, in the presence of anicotine-induced steroid resistance, promotes inflammationprooxidatively. Accordingly, in the future a new importance may beattributed to the substance 1,8-cineol. Moreover, owing to a confirmedlocal and systemic inflammatory reaction, COPD cannot be treatedsatisfactorily by an inhalative combined therapy alone, so that furtherfoundations for new core statements with respect to the active compound1,8-cineol are increasingly being developed by the external support ofworld-wide research efforts, which will have to be implemented in anappropriate manner.

In summary, the present data open up a very current and hithertounderestimated perspective which helps in the understanding of the novelrange of indications for 1,8-cineol on a local level in spite ofsystemic administration. At the same time, this also provides newoptions as the compatibility has to be looked at as a consequence ofinteractions with different comedications. The adopted procedure willhelp in the correct assessment of the substance 1,8-cineol with respectto its action and the clinical use for respiratory disorders that can bederived therefrom.

TABLE 6 Additive effect of 1,8-cineol (0.9 μg/ml) and beclometasone(“becl.”) on the FCS-stimulated superoxide production of normal humanmonocytes in vitro O₂ ⁻ Percent mol/l n (nmol/ml) of control p-Valuespontaneous 11 11050 ± 1102 — — FCS 10% 11 18778 ± 1178 — 0.00091,8-cineol 11 9347 ± 494 −50.2 ± 5     <0.0001 6 × 10⁻⁶ becl. 10⁻¹¹ 1117639 ± 1372 −6 ± 8   0.3088 becl. 10⁻¹⁰ 11 17577 ± 1191 −6 ± 7   0.5545becl. 10⁻⁹ 12 17338 ± 1305 −8 ± 7   0.5767 1,8-cineol + 11 9395 ± 493−49.9 ± 5     <0.0001 becl. 10⁻¹¹ 1,8-cineol + 11 11099 ± 386  −40.9 ±3     <0.0001 becl. 10⁻¹⁰ 1,8-cineol + 11 11626 ± 369  −38.1 ± 3    <0.0001 becl. 10⁻⁹

1. The use of at least one systemically administrable, in particularoral, monoterpene and at least one topically administrable, inparticular inhalative, respiratory therapeutic for the prophylacticand/or therapeutic treatment, in particular combination therapy and/orcomedication, of respiratory disorders, in particular bronchopulmonarydisorders.
 2. The use as claimed in claim 1, characterized in that themonoterpene is selected from mono- and bicyclic monoterpenes, inparticular from the group consisting of monocyclic monoterpene alcohols,preferably menthol, in particular L-menthol, and bicyclicepoxy-monoterpenes, preferably limonene oxides, preferably 1,8-cineol,and also mixtures thereof, particularly preferably from the groupconsisting of menthol and 1,8-cineol, very particularly preferably1,8-cineol, and/or that the monoterpene is 1,8-cineol.
 3. The use asclaimed in claim 1 or 2, characterized in that the monoterpene ispresent in an oral administration form, preferably in the form ofcapsules, and/or that the monoterpene is present in the form of an oralenteric preparation, in particular capsule, which does dissolve in thesmall intestine.
 4. The use as claimed in any of the preceding claims,characterized in that the monoterpene is administered in daily doses offrom 100 to 2000 mg/die, in particular from 200 to 1200 mg/die,preferably from 300 to 1000 mg/die, and/or that the monoterpene isprepared for administration in a daily dose of from 100 to 2000 mg/die,in particular from 200 to 1200 mg/die, preferably from 300 to 1000mg/die.
 5. The use as claimed in any of the preceding claims,characterized in that the monoterpene is 1,8-cineol, where 1,8-cineol isemployed in particular in the form of enteric capsules which dissolve inthe small intestine, preferably in daily doses of from 100 to 2000mg/die, in particular from 200 to 1200 mg/die, particularly preferablyfrom 300 to 1000 mg/die.
 6. The use as claimed in any of the precedingclaims, characterized in that the respiratory therapeutic to beadministered topically is an inhalative respiratory therapeutic.
 7. Theuse as claimed in any of the preceding claims, characterized in that therespiratory therapeutic to be administered topically, in particularinhalatively, is selected from bronchodilators and bronchospasmolyticsand/or the respiratory therapeutic to be administered topically, inparticular inhalatively, is selected from the group consisting of (i)corticosteroids, in particular glucocorticoids; (ii) sympathomimetics,in particular betasympathomimetics, preferably beta-2-sympathomimetics;(iii) phosphodiesterase inhibitors; (iv) parasympatholytics and/orvagolytics; (v) anticholinergics; and also mixtures and combinations ofthe compounds mentioned above, and is particularly preferably selectedfrom the group consisting of corticosteroids, in particularglucocorticoids, beta-2-sympathomimetics and anticholinergics and alsomixtures and combinations thereof.
 8. The use as claimed in any of thepreceding claims, characterized in that the respiratory therapeutic tobe administered topically, in particular inhalatively, is acorticosteroid, in particular glucocorticoid, preferably selected fromthe group consisting of beclometasone, mometasone, budesonide,flunisolide, fluticasone, triamcinolone and their physiologicallyacceptable derivatives, in particular salts and esters, and alsomixtures and combinations of the compounds mentioned above, where thecorticosteroid is administered in particular in daily doses of from 50to 1000 μg/die, in particular from 75 to 800 μg/die, particularlypreferably from 100 to 600 μg/die, and/or is prepared in particular foradministration in a daily dose of from 50 to 1000 μg/die, in particularfrom 75 to 800 μg/die, particularly preferably from 100 to 600 μg/die.9. The use as claimed in any of the preceding claims, characterized inthat the respiratory therapeutic to be administered topically, inparticular inhalatively, is a sympathomimetic, in particularbetasympathomimetic, preferably beta-2-sympathomimetic, in particularselected from the group consisting of short-acting betamimetics (SABA),in particular albuterol, fenoterol, hexoprenalin, levalbuterol,metaproterenol, orciprenalin, pirbuterol, reproterol, salbutamol and/orterbutalin, and long-acting betamimetics (LABA), in particularsalmeterol and/or formoterol.
 10. The use as claimed in any of thepreceding claims, characterized in that the respiratory therapeutic tobe administered topically, in particular inhalatively, is ananticholinergic, in particular from the group consisting of ipratropium,tiotropium and/or their physiologically acceptable derivatives,preferably salts, particularly preferably ipratropium bromide and/ortiotropium bromide.
 11. The use as claimed in any of the precedingclaims, characterized in that additionally at least one furthersystemic, in particular oral, active compound is administered, inparticular selected from the group consisting of systemicphosphodiesterase inhibitors, in particular theophylline; systemicleukotriene receptor antagonists, in particular montelukast, zaforlukastand pranlukast; systemic corticosteroids; and also mixtures andcombinations thereof.
 12. The use as claimed in any of the precedingclaims, characterized in that the bronchopulmonary disorder is aninflammatory or non-inflammatory, in particular inflammatory, disorderof the upper or lower respiratory tract.
 13. The use as claimed in anyof the preceding claims, characterized in that the bronchopulmonarydisorder is an inflammatory respiratory disorder, in particular arespiratory disorder which is infection-exacerbated and/or requiressteroids for treatment.
 14. The use as claimed in any of the precedingclaims, characterized in that the bronchopulmonary disorder is bronchialasthma or bronchitis.
 15. The use as claimed in any of the precedingclaims, characterized in that the bronchopulmonary disorder is a chronicobstructive pulmonary disorder (COPD), in particular a chronicobstructive bronchitis or a pulmonary emphysema.
 16. The use as claimedin any of the preceding claims, characterized in that thebronchopulmonary disorder is a tobacco smoke-induced, in particularnicotine-induced, acute or chronic respiratory inflammation.
 17. The useas claimed in any of the preceding claims, characterized in that thebronchopulmonary disorder is an early form of COPD, in particular stage0 or I according to GOLD, or an early form of bronchial asthma, inparticular stage 0 or I according to GINA.
 18. The use as claimed in anyof the preceding claims for treating an early form of COPD, inparticular stage 0 or I according to GOLD, or an early form of bronchialasthma, in particular stage 0 or I according to GINA, in particular forexacerbation prophylaxis before or after exacerbation and/or forprevention or slowing down of the progression of the disease before orafter exacerbation.
 19. The use of at least one systemicallyadministrable, in particular oral, monoterpene, preferably 1,8-cineol,in particular as claimed in any of the preceding claims, for the inparticular synergistic enhancement of the activity of at least onetopically administrable, in particular inhalative, respiratorytherapeutic in the prophylactic and/or therapeutic treatment ofrespiratory disorders, in particular bronchopulmonary disorders.
 20. Theuse of at least one systemically administrable, in particular oral,monoterpene, preferably 1,8-cineol, in particular as claimed in any ofthe preceding claims, for the in particular synergistic enhancement ofthe anti-inflammatory and/or antioxidative activity of topical, inparticular inhalative, corticosteroids, in particular glucocorticoids.21. The use of at least one systemically administrable, in particularoral, monoterpene, preferably 1,8-cineol, in particular as claimed inany of the preceding claims, for reducing the dose of topicallyadministrable, in particular inhalative, respiratory therapeutics,preferably inhalative corticosteroids, in the prophylactic and/ortherapeutic treatment of respiratory disorders, in particularbronchopulmonary disorders.
 22. The use of at least one systemicallyadministrable, in particular oral, monoterpene, preferably 1,8-cineol,in particular as claimed in any of the preceding claims, for inducingand/or enhancing the steroid-permissive effect of topicallyadministrable, in particular inhalative, respiratory therapeutics,preferably inhalative corticosteroids, in the prophylactic and/ortherapeutic treatment of respiratory disorders, in particularbronchopulmonary disorders.
 23. The use of at least one systemicallyadministrable, in particular oral, monoterpene, preferably 1,8-cineol,in particular as claimed in any of the preceding claims, for avoiding orreducing habituation to betasympathomimetics in the prophylactic and/ortherapeutic treatment of respiratory disorders, in particularbronchopulmonary disorders, in particular with continuous therapy of alldegrees of severity of COPD and bronchial asthma.
 24. The use of atleast one systemically administrable, in particular oral, monoterpene,preferably 1,8-cineol, in particular as claimed in any of the precedingclaims, in combination with at least one topically administrable, inparticular inhalative, respiratory therapeutic, in particular incombination with an inhalative corticosteroid, for reducing the need foror for replacing systemic corticosteroids or other anti-inflammatoryand/or immunosuppressive systemic substances in the prophylactic and/ortherapeutic treatment of respiratory disorders, in particularbronchopulmonary disorders.
 25. The use of at least one systemicallyadministrable, in particular oral, monoterpene, preferably 1,8-cineol,in particular as claimed in any of the preceding claims, in combinationwith at least one topically administrable, in particular inhalative,respiratory therapeutic, in particular in combination with an inhalativecorticosteroid and optionally with an inhalative beta-2-sympathomimetic,to optimize the basic therapy of bronchial asthma and COPD.
 26. The useas claimed in any of the preceding claims to treat systemicsimultaneously affected organs in all severe forms of COPD.
 27. The useas claimed in any of the preceding claims for modulating and inhibitingCOPD-dependent and/or COPD-independent ageing processes, in particularwith the aim of reducing morbidity, increasing the quality of lifeand/or life expectancy.
 28. The use as claimed in any of the precedingclaims, characterized in that the monoterpene, in particular 1,8-cineol,is used as an inducer of NO-production for the treatment of primary andsecondary pulmonary-arterial hypertension (PAH) in COPD and bronchialasthma.
 29. The use as claimed in any of the preceding claims,characterized in that the monoterpene, in particular 1,8-cineol, is usedfor improving tissue perfusion and/or microperfusion and alsobronchodilation in NO-deficiency situations.
 30. The use as claimed inany of the preceding claims, characterized in that the monoterpene, inparticular 1,8-cineol, is used for inducing NO-production in recurrentinfections of the upper and lower respiratory tracts or ininfection-independent exacerbations, in particular owing to cigarettesmoking and/or the action of ozone, or for normalizing noxioussubstance-dependent or -independent NO-deficiency situations.
 31. Theuse as claimed in any of the preceding claims, characterized in that themonoterpene, in particular 1,8-cineol, is used as an antioxidant and/orNO-inducer in cigarette smoke-induced organ damage, in particular of thelung, the heart, the brain, the kidneys and the venous and arterialvascular system.
 32. The use as claimed in any of the preceding claims,characterized in that the monoterpene, in particular 1,8-cineol, is usedfor the combined anti-inflammatory and/or antioxidative therapy of thepersistent and/or progressive inflammation of the respiratory tractafter cessation of smoking, if appropriate with comedication with otherrespiratory therapeutics, in particular with the aim of delaying thedevelopment of emphysemas, respiratory insufficiency and/or thedevelopment of peripheral airway obstructions.
 33. The use as claimed inany of the preceding claims, characterized in that the monoterpene, inparticular 1,8-cineol, is used for modulating the entire multiorganageing process by virtue of anti-inflammatory and/or antioxidativeeffects in an early long-term therapy.
 34. The use of at least onesystemically administrable, in particular oral, monoterpene and at leastone topically administrable, in particular inhalative, respiratorytherapeutic as combination therapeutic and/or for the purpose ofcomedication for the prophylactic and/or therapeutic treatment ofrespiratory disorders, in particular bronchopulmonary disorders.
 35. Theuse of at least one systemically administrable, in particular oral,monoterpene and at least one topically administrable, in particularinhalative, respiratory therapeutic for preparing a combinationtherapeutic, in particular in the form of a kit, for the prophylacticand/or therapeutic treatment of respiratory disorders, in particularbronchopulmonary disorders.
 36. A combination therapeutic, in particularin the form of a kit, preferably for the prophylactic and/or therapeutictreatment of respiratory disorders, in particular bronchopulmonarydisorders, comprising, firstly, at least one systemically administrable,in particular oral, monoterpene and, secondly, at least one topicallyadministrable, in particular inhalative, respiratory therapeutic.
 37. Amethod for treating the human or animal body, in particular a method forthe prophylactic and/or therapeutic treatment of respiratory disorders,in particular bronchopulmonary disorders, where at least one monoterpeneand at least one respiratory therapeutic are each used in effective, inparticular pharmaceutically effective, amounts, where the monoterpene isadministered systemically, in particular orally, and the respiratorytherapeutic is administered topically, in particular inhalatively. 38.The use of at least one systemically administrable, in particular oral,monoterpene, preferably 1,8-cineol, for the prophylactic and/or curativetreatment of respiratory disorders, in particular bronchopulmonarydisorders, in smokers and/or former smokers and for the preparation of amedicament for the prophylactic and/or curative treatment of respiratorydisorders, in particular bronchopulmonary disorders, in smokers orformer smokers, where the monoterpene can be employed in particulartogether with at least one topically administrable, in particularinhalative, respiratory therapeutic, in particular as a combinationtherapy and/or in comedication.
 39. The use of at least one systemicallyadministrable, in particular oral, monoterpene, preferably 1,8-cineol,for the prophylactic and/or curative treatment of antioxidative and/oranti-inflammatory processes in the human body in particular of smokersor for preparing a medicament for the prophylactic and/or curativetreatment of antioxidative and/or anti-inflammatory processes in thebody in particular of smokers, where the monoterpene can be employed inparticular together with at least one topically administrable, inparticular inhalative, respiratory therapeutic, in particular as acombination therapy and/or in comedication.
 40. The use of at least onesystemically administrable, in particular oral, monoterpene, preferably1,8-cineol, for increasing the corticosteroid sensitivity of smokers, inparticular for the prophylactic and/or therapeutic treatment ofrespiratory disorders, in particular bronchopulmonary disorders, wherethe monoterpene can be employed in particular together with at least onetopically administrable, in particular inhalative, respiratorytherapeutic, in particular as a combination therapy and/or incomedication.
 41. The use as claimed in any of claims 38 to 40,characterized in that the monoterpene is selected from mono- andbicyclic monoterpenes, in particular from the group consisting ofmonocyclic monoterpene alcohols, preferably menthol, in particularL-menthol, and bicyclic epoxy-monoterpenes, preferably limonene oxides,preferably 1,8-cineol, and also mixtures thereof, particularlypreferably from the group consisting of menthol and 1,8-cineol, veryparticularly preferably 1,8-cineol, and/or that the monoterpene is1,8-cineol and/or that the monoterpene is present in an oraladministration form, preferably in the form of capsules, and/or that themonoterpene is present in the form of an oral enteric preparation, inparticular capsule, which does dissolve in the small intestine and/orthat the monoterpene is administered in daily doses of from 100 to 2000mg/die, in particular from 200 to 1200 mg/die, preferably from 300 to1000 mg/die, and/or that the monoterpene is prepared for administrationin a daily dose of from 100 to 2000 mg/die, in particular from 200 to1200 mg/die, preferably from 300 to 1000 mg/die.
 42. The use as claimedin any of claims 38 to 41, characterized by one or more of the featuresof claims 1 to 37.